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Review

Targeting Inflammatory Pathways by Triterpenoids for Prevention and Treatment of Cancer

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston 77030, TX, USA
*
Author to whom correspondence should be addressed.
Submission received: 30 August 2010 / Revised: 23 September 2010 / Accepted: 15 October 2010 / Published: 22 October 2010

Abstract

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Traditional medicine and diet has served mankind through the ages for prevention and treatment of most chronic diseases. Mounting evidence suggests that chronic inflammation mediates most chronic diseases, including cancer. More than other transcription factors, nuclear factor-kappaB (NF-κB) and STAT3 have emerged as major regulators of inflammation, cellular transformation, and tumor cell survival, proliferation, invasion, angiogenesis, and metastasis. Thus, agents that can inhibit NF-κB and STAT3 activation pathways have the potential to both prevent and treat cancer. In this review, we examine the potential of one group of compounds called triterpenes, derived from traditional medicine and diet for their ability to suppress inflammatory pathways linked to tumorigenesis. These triterpenes include avicins, betulinic acid, boswellic acid, celastrol, diosgenin, madecassic acid, maslinic acid, momordin, saikosaponins, platycodon, pristimerin, ursolic acid, and withanolide. This review thus supports the famous adage of Hippocrates, “Let food be thy medicine and medicine be thy food”.

1. Introduction

Natural compounds have been used extensively in the treatment of many diseases and are of interest to researchers both in their natural forms and as templates for synthetic modification. Natural compounds currently used in medicine exhibit a very wide chemical diversity, and together with their analogues and several other natural products, they demonstrate the importance of compounds from natural sources in modern drug discovery efforts. Sample sources and molecular mechanisms are highly important in the development of novel, clinically useful anticancer agents [1]. Interest in natural compounds has grown in recent years because of concerns about drug costs and safety. For example, glioblastoma kills almost everyone who gets it, usually in a little over a year. In effect, the $1.3 billion spent by a pharmaceutical company on a new glioblastoma drug discovery had the limited impact of improving patients’ lives for about one year. This illustrates the need for new sources for drug discovery, and natural sources provide valuable information for research in this area. During the past decade, tremendous progress has been made toward understanding the cellular and molecular mechanisms underlying the process of carcinogenesis, leading to the development of potential cancer prevention options termed chemoprevention [2]. The goal of chemoprevention is to use noncytotoxic natural agents to inhibit or reverse the development and progression of precancerous cells [3].
Cancer is a complicated disease that may develop in humans over a number of years (Figure 1). Development of a tumor starts with a normal cell that is transformed through the activation of proto‑oncogenes and the suppression of tumor suppressor genes such as p53. The transformed cell no longer behaves like a normal cell but begins to exhibit the properties of a cancer cell. Such transformation in the cells makes them self-sufficient in growth signals and resistant to antigrowth signals, resulting in uncontainable proliferation. In addition, these cells are able to avoid apoptosis, resulting in tumor growth. This whole process of transformation may take 10–20 years. The growth of the tumor is aided by angiogenesis, which not only provides nutrition to the tumor but also enables its invasion to surrounding tissues, and its metastasis to distant tissues; the latter is usually lethal.
Figure 1. Roles of the NF-κB-mediated inflammatory pathway in cellular transformation and in cancer cell survival, proliferation, invasion, angiogenesis, and metastasis.
Figure 1. Roles of the NF-κB-mediated inflammatory pathway in cellular transformation and in cancer cell survival, proliferation, invasion, angiogenesis, and metastasis.
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Inflammation, which occurs as a response to cancer, has two stages, acute and chronic. Acute inflammation, the initial stage of inflammation, represents innate immunity; it is mediated through the activation of the immune system, lasts for a short period and generally is regarded as therapeutic inflammation. If the inflammation persists for a long period of time, however, the second stage, chronic inflammation, sets in [4]. Chronic inflammation has been linked with most chronic illnesses, including cancer, cardiovascular disease, diabetes, obesity, pulmonary disease, and neurologic disease [5], the current review focuses on the role of triterpenoids in targeting inflammatory pathways for prevention and treatment of cancer.
Evidence from tissue culture, animal, and clinical studies suggests that more than 20,000 triterpenoid-rich fruits are found in nature and have the potential ability to limit the development and severity of certain cancers and inflammatory diseases [6]. These triterpenoids, along with their close chemical relatives the steroids, are members of a larger family of related structures called cyclosqualenoids. Triterpenoids, synthesized in many plants by the cyclization of squalene [7], are widely used in Asian medicine. More than 100 prescribed drugs in the United States are obtained from natural sources and represent one fourth of the total drugs used. Apart from these drugs that originate from natural sources, other phytochemicals also serve as potential drugs after structural modification [8].
Figure 2. Triterpenoids and their sources.
Figure 2. Triterpenoids and their sources.
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Scientific studies have shown triterpenoids to be potential anti-inflammatory and anticancer agents. This review covers the anti-inflammatory and anticancer property of triterpenoids originating from plants such as onion, ginseng, brahmi, azuma ichirinsou, shallaki, salai guggal, lei gong teng, licorice, mango, olive, bearberry, Chinese bellflower, sickle-leaf, tulsi, ashwagandha, and others (Figure 2 and Table 1) that target one or more of the various phases of tumorigenesis. As more than 20,000 triterpenoids are available in nature and it is difficult to describe them all, this review summarizes what we know of a few triterpenoids with structural similarity, including avicin, erythrodiol, madecassic acid, maslinic acid, momordin, saikosaponins, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its methyl ester CDDO-Me, platycodon D, withanolide, diosgenin, betulinic acid, boswellic acids, pristimerin, and celastrol (Figure 3); their active moieties for anti-inflammatory and anticancer activity.
Figure 3. Chemical structures of different types of triterpenoids that inhibit NF-κB.
Figure 3. Chemical structures of different types of triterpenoids that inhibit NF-κB.
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Table 1. Common medicinally active triterpenoid obtained from plants.
Table 1. Common medicinally active triterpenoid obtained from plants.
Chemical Compound Common NameBotanical Name
Tetracyclic triterpenoid
Astragaloside Chinese milk vetch Astragalus membranaceus
Cucurbitacin White bryony Bryonia alba
Diosgenin Fenugreek Trigonella foenum graecum
Ganoderic acidReishi Ganoderma lucidum
Ginsenoside Ginseng Panax ginseng
Gypenoside Jiaogulan Gynostemma pentaphyllum
OleandrinOleander Nerium oleander
Pentacyclic triterpenoid
Amyrin Japanese persimmon Diospyros kaki
Asiatic acid Indian pennywortCentella asiatica
AvicinElegant wattle Acacia victoriae
Betulinic acid Indian jujubeZiziphus mauritiana
Anemone Anemone raddeana
Club mosses Lycopodium cernuum
Trumpet satinash Syzygium claviflorum
Boswellic acidBoswellia,Boswellia serrata
Frankincense, salai guggal Boswellia carteri
CelastrolThunder god vine Tripterygium wilfordii
EscinHorse chestnutAesculus hippocastanum
Glycyrrhizin Licorice Glycyrrhiza glabra
18-β-Glycyrrhetinic acidLicorice Glycyrrhizia glabra
Lupeol Mango Mangifera indica
Three leaved caper Crataeva nurvala
Madecassic acidIndian pennywort, gotu kolaCentella asiatica
MomordinBurning bushKochia scoparia
Oleanolic acid Bearberry Arctostaphyllos uva-ursi
Heather Calluna vulgaris
Three leaved caper Crataeva nurvala
Reishi Ganoderma lucidum
Chinese elderSambucus chinensis
Sodom's appleSolanum incanum
Platycodon D Balloon flowerPlatycodon grandiflorum
PristimerinEspinheira santa Maytenus ilicifolia
Pale BittersweetCelastrus hypoleucus
Thunder god vine Tripterygium wilfordii
SaikosaponinsHare's ear root, sickle-leafBupleurum falcatum L.
Ursolic acid Holy basil, tulsiOcimum sanctum L.
ThymeThymus vulgaris L.
LavenderLavandula augustifolia
Catnip Nepeta sibthorpii
Peppermint leaves Mentha piperita L.
WithanolideIndian ginseng, ashwagandhaWithania somnifera
The review also focuses on targets for inflammation, proliferation, apoptosis, invasion, metastasis and angiogenesis. Because a large portion of these nutraceuticals show great potential for targeting cancer through various mechanisms—such as the downregulation of transcription factors (e.g., nuclear factor-kappaB [NF-κB]), anti-apoptotic proteins (e.g., bcl-2, bcl-xL), promoters of cell proliferation (e.g., cyclooxygenase-2 [COX-2], cyclin D1, c-myc), invasive and metastatic genes (e.g., matrix metalloproteinases [MMPs], intracellular adhesion molecule-1 (ICAM-1), and angiogenic protein (vascular endothelial growth factor (VEGF)) (Table 2); and other uses of these triterpenoids are shown in Table 3. This review summarizes the sources and structures of triterpenoids and provides insight into the underlying molecular targets for cancer prevention and therapy.
Table 2. Molecular targets of triterpenoid for anticancer and anti-inflammatory activities.
Table 2. Molecular targets of triterpenoid for anticancer and anti-inflammatory activities.
TriterpenoidTargets References
AmyrinNF-κB, IL-1β, COX-2, CREB, ERK, PKC, P38 MAPK[9,10]
AvicinNF-κB, Fas, STAT3, caspase-8, Bcl-2, Bcl-xL[11,12,13,14,15,16]
Asiatic acidNF-κB, caspases-2, -3, -8 and -9, PARP, Bcl-2[17,18,19,20,21,22,23,24]
AstragalosideNF-κB, VCAM-1 [25]
Betulinic acidNF-κB, STAT3, Bax, Bcl-2, Bcl-xL, FAK[26,27,28,29,30,31,32,33,34,35,36,37,38]
Boswellic acidNF-κB, STAT3, AR, p21, DR5, caspase-3 and -8[32,39,40,41,42,43,44,45,46,47,48]
CelastrolNF-κB, IAP1, IAP2, Bcl-2, Bcl-xL, c-FLIP, COX-2, survivin, cyclin D1, MMP9, VEGF, iNOS, Hsp90, cdc37, VEGFR[49,50,51,52,53]
CucurbitacinCyclin B1, cyclin D1, Mcl-1, cdc25C, STAT3, p53[54,55,56,57,58,59]
DiosgeninNF-κB, survivin, XIAP, cyclin D1, cdk-2, cdk-4, mTOR, JNK, HMG-CoA reductase, p53, AIF, p21 ras, β-catenin [60,61,62,63,64,65]
EscinNF-κB, STAT3, JAK2, cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1, VEGF, COX-2, MMP9[66,67]
Ganoderic acidNF-κB, AP-1, NFATc1, cdk4, uPA, MMP2, MMP9,[68,69,70,71,72]
GinsenosidesNF-κB, Bax, caspase-3, caspase-8, Bcl-2, IAP, XIAP, cyclin B1, cyclin D, cdk2, cdk4, VEGF, MAPK, IL-1β, TNF-α, ICAM-1, JNK[73,74,75,76]
GlycyrrhizinNF-κB, AP-1, TLR2, COX-2, IL-1α, TNF-α [77,78,79,80,81,82,83]
Glycyrrhetinic acidNF-κB, H-ras, Bax, cytochrome C, Bcl-2, Bcl-xL, Bak, caspase-3, PPARγ[84,85,86]
GypenosideNF-κB, PPAR , VCAM-1, TF, iNOS, Ras[87,88,89,90,91,92]
LupeolNF-κB, cFLIP, survivin, Bax, caspase-3, caspase-9[93,94,95,96,97,98,99,100,101,102]
Madecassic acidiNOS, COX-2, TNF-α, IL-1, IL-6[103]
MomordinNF-κB, AP-1, Bcl-2, Bax, caspase-3, PARP [104,105]
OleandrinNF-κB, AP-1, Fas, ERK, Akt, FGF-1[106,107,108,109,110]
Oleanolic acidNF-κB, mTOR, caspases-3, -8, and -9, ICAM-1, VEGF, PARP, Akt[111,112,113,114]
Platycodon DNF-κB, Egr-1, caspase-3[115,116]
PristimerinNF-κB, PARP-1, JNK, Bax, p27, Bcl-2, Bcl-xL[117,118,119,120]
SaikosaponinsNF-κB, NF-AT, AP-1, IL-6, TNF- , IFN- , PKC , JNK, p53, Fas/FasL[121,122,123]
Ursolic acidNF-κB, STAT3, Bcl-2, Bax, ICAM-1, p53, PKC[114,124,125,126,127,128,129,130,131,132]
WithanolideNF-κB, AP-1, IL-6, COX-2, Hsp70, Hsp90, Bax[133,134,135,136,137,138]
AIF, apoptosis inducing factor; AMPK, 5' AMP-activated protein kinase; AP-1, activator protein-1; Apaf1, apoptotic protease activating factor 1; AR, androgen receptor; Bax, BCL2-associated X protein; Bfl-1/A1, BCL2-related protein A1; cdc, cell division cycle; cdk, cyclin-dependent kinase; cFLIP, cellular FLICE inhibitory protein; COX-2, cyclooxygenase-2; CREB, cAMP response element binding protein; DR, death receptor; EGFR, epidermal growth factor receptor; Egr-1, earyl growth response factor-1; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; FasL, Fas-ligand; FGF-1, fibroblast growth factor-1; GSK3β, glycogen synthase kinase-3β; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; Hsp, heat shock protein; IAP, inhibitor of apoptosis protein; ICAM-1, intercellular adhesion molecule-1; IFN-γ, interferon-γ; IL‑1, interleukin-1; iNOS, inducible nitric oxide synthase; JNK, c-Jun N-terminal kinase; MAPK, mitogen–activated protein kinase; Mcl-1, myeloid cell leukemia-1; MCP, monocyte chemotactic protein; MEK, MAPK/ERK kinase, MIP-2, macrophage-inflammatory protein-2; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; NF-AT, nuclear factor of activated T-cells; NF–κB, nuclear factor–kappa B; PARP, poly (ADP-ribose) polymerase; PI3K, phosphoinositide-3 kinase; PKC, protein kinase C; PPAR, peroxisome proliferator–activated receptor; Sp1, specificity protein 1; STAT3, signal transducer and activator of transcription 3; TF, tissue factor; TLR2, Toll-like receptor-2; TNF-α, tumor necrosis factor-α; TRAF1, TNF receptor-associated factor-1; uPA, urokinase-type plasminogen activator; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; XIAP, X-linked IAP.
Table 3. Other uses of triterpenoid in treatment of chronic diseases.
Table 3. Other uses of triterpenoid in treatment of chronic diseases.
DiseaseTriterpenoid
DiabetesAstragaloside, Cucurbitacin, Diosgenin, Ginsenoside, Amyrin, Asiatic acid, Avicin, Betulinic acid, Escin, Glycyrrhizin, Oleanolic acid, Platycodon D, Ursolic acid, Withanolide
CardiovascularAstragaloside, Cucurbitacin, Diosgenin, Ginsenoside, Gypenoside, Oleandrin, Betulinic acid, Escin, Glycyrrhizin, Lupeol, Oleanolic acid, Platycodon D, Saikosaponins, Ursolic acid, Withanolide
Arthritis Cucurbitacin, Diosgenin, Ginsenoside, Amyrin, Boswellic acid, Celastrol, Glycyrrhizin, Lupeol, Oleanolic acid, CDDO-Me, Ursolic acid, Withanolide,
AtherosclerosisDiosgenin, Gypenoside, Betulinic acid, Glycyrrhizin, Oleanolic acid, Ursolic acid
ObesityDiosgenin, Ginsenoside, Betulinic acid, Escin, Glycyrrhizin, Platycodon D, Momordin, Oleanolic acid, Ursolic acid
AlzheimerCDDO-MA, Alpha-onocerin
Parkinson CDDO-MA
Multiple sclerosisOleanolic acid
DepressionAsiatic acid
OsteoporosisUrsolic acid
Cerebral ischemiaEscin, Asiatic acid
Memory lossCDDO-MA

2. Source and Structure of Triterpenoids

Triterpenoids are metabolites of isopentenyl pyrophosphate oligomers that are chemically related to squalene, which is a large group of compounds having 30 carbon atoms arranged in five rings with several oxygen atoms attached. Triterpenoids are part of the largest group of plant products, Saponins can be chemically biosynthesized when one or more sugar moieties attach to aglycone. There are two types of saponins, steroidal aglycone and triterpenoid aglycone. Both steroid and triterpenoid systems are found to be biosynthesized from a common precursor such as squalene [139]. Triterpenoids are synthesized from isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP). For this cyclization, three prenyltransferases synthesize the linear prenyl pyrophosphates geranyl pyrophosphate (GPP), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP). Squalene is in turn derived biosynthetically by the cyclization of a number of units of isoprene, (C5H8)n, which undergo folding through 20 different patterns in the presence of prenyl pyrophosphates to form monocyclic, dicyclic, tricyclic, tetracyclic, or pentacyclic derivatives [140]. A family of oxidosqualene cyclases may produce only a single product, such as lupeol cyclases, but there are also multifunctional oxidosqualene cyclases that use dammarenyl cation intermediates to produce many products. Once squalene undergoes cyclization, it goes through the cytosolic mevalonate pathway to make a proximate tetracyclic C30 compound, lanosterol (Figure 4), which further undergoes oxidation and catabolic metabolism to form cholesterol.
Figure 4. Different patterns of cyclization of squalene to form triterpenoids. (IPP, isopentenyl pyrophosphate; DMAPP, dimethylallyl pyrophosphate).
Figure 4. Different patterns of cyclization of squalene to form triterpenoids. (IPP, isopentenyl pyrophosphate; DMAPP, dimethylallyl pyrophosphate).
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The variety of triterpenoids in nature is a result of the evolution of a large terpene synthase superfamily. One study analyzed the amino acid sequences of terpene synthase genes and found that all originated from an ancestral diterpene synthase. It was also found that the diversity of these triterpenoids is due to the structural features of their catalyst enzymes. Terpenes and their metabolites are widely distributed in various plant systems that depend on various biotic and abiotic environmental factors. Terpenes and their metabolites are used in several developmental and physiological functions on the basis of the differential expression profiles of terpene synthase genes. Terpenes and their metabolites play a very important role in a plant’s defense mechanism. They protect the plants from both constitutive and induced defensive responses against insects and environmental stress [141,142]. Hence, triterpenoids provide a very good protection shield for plants, indicating their potential for use in the prevention of various cancers and inflammatory diseases in humans.

3. Molecular Targets of Triterpenoids

In 1856, Rudolf Virchow for the first time showed inflammation to be a predisposing factor for various types of cancer. Today, the data suggest that at least one in seven malignant tumors diagnosed worldwide results from chronic inflammation and infection. Recognition of this fact has led to greater interest in research for molecular targets involved in the inflammatory pathways that trigger cancer and to find novel markers that restrain cancer progression along these pathways.
The conventional methods of treatment of cancer include surgery, chemotherapy and/or radiotherapy; the mode of treatment depends largely upon the type of cancer the patient has. Innovative, so-called multitargeting therapies from natural resources are urgently needed to target the various steps of cancer progression or the processes involved in cancer cell survival and metastasis to other parts of the body.
It is clear now that cancer is not a simple disease involving a single gene, but a complex disease involving interaction between multiple genes, either within the same cell or with those of neighboring tissues. The prevention or progression of human cancer depends on the integrity of a complex network of defense mechanisms in which 300–500 genes have gone wrong, leading to the upregulation of undesired products such as antiapoptotic proteins or the downregulation of tumor suppressor proteins.

3.1. NF-κB

NF-κB, a ubiquitous transcription factor, was discovered in 1986 as a nuclear factor that binds to the enhancer region of the κB chain of immunoglobulin in B cells. It is present in all cells, and in its resting stage, this factor resides in the cytoplasm as a heterotrimer consisting of p50, p65, and inhibitory subunit IκBα. NF-κB is activated by free radicals, inflammatory stimuli, cytokines, carcinogens, tumor promoters, endotoxins, γ-radiation, ultraviolet light, and x-rays [143]. On activation, the IκBα protein, an inhibitor of NF-κB, undergoes phosphorylation, ubiquitination, and degradation. p50 and p65 are then released to be translocated to the nucleus, bind to specific DNA sequences present in the promoters of various genes, and initiate the transcription of more than 400 genes. The kinase that causes the phosphorylation of IκBα is called IκBα kinase (IKK). Whereas the IKKβ mediates the classic/canonical NF-κB activation pathway, the IKKκ mediates the noncanonical pathway. IKK itself must be activated before it can activate IκBα. More than a dozen kinases have been described that can activate IKK, including protein kinase B (Akt), mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEKK1), MEKK3, transforming growth factor (TGF)–activating kinase 1 (TAK1), NF-κB–activating kinase, NF-κB–inducing kinase, protein kinase C, and the double-stranded RNA-dependent protein kinase (PKR).

3.2. STAT3

Signal transducer and activator of transcription 3 (STAT3), one of the major molecular targets of triterpenoids, was first identified in 1994 as a DNA-binding factor that selectively binds to the IL‑6‑responsive element in the promoter. The activation of STAT3 is regulated by the phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases, including epidermal growth factor receptor (EGFR) kinase [144], Src [145], Janus-activated kinases (JAK) [146,147], and extracellular signal-regulated kinase (ERK) [148]. The phosphorylation of STAT3 in the cytoplasm leads to its dimerization, translocation into the nucleus, and DNA binding, which results in the regulation of several genes involved in cell proliferation, differentiation, and apoptosis.

3.3. Other Pathways

A large body of evidence signifies the role of inflammation in cancer development through mediators such as reactive oxygen species (ROS), free radicals, and inflammatory cytokines like tumor necrosis factor-α (TNFα), lymphotoxins, and angiogenic factors. Also known to influence oncogenesis are signaling pathways that in normal cells are involved in tissue homeostasis, such as the NF-κB, prostaglandin/cyclooxygenase-2 (COX-2), and p53 pathways; the DNA repair machinery; and a family of the Toll-like receptor proteins.
Some of the most commonly known molecular targets of triterpenoids involved in the treatment and prevention of cancer have been targeted according to comprehensive knowledge of tumor growth and metastasis. This approach will maximize the effect of triterpenoids and minimize side effects by multitargeting the cells or processes that enable cancer to survive and spread in humans.

4. Role of Triterpenoids in Cancer Prevention

4.1. Role of Triterpenoids in Inflammation

Inflammation is derived from the Latin word ‘inflammare or inflammatio’, which means, “to set on fire.” Inflammation is a basic defense mechanism in which the body reacts against infections, irritations, or other injuries. The four key features of inflammation are redness, heat, swelling, and pain. Inflammation stimulates the immune response at the site of injury or infection and is itself stimulated by increases in blood supply and vascular permeability, which allow more infiltration of plasma and leukocytes from the blood into injured tissues. This particular type of immune response is important because it helps the body to ward off pathogens and also to initiate the healing process in the damaged tissues. This reaction is classified as acute inflammation. Studies have shown that chronic inflammation is a progenitor of tumor progression and that many cancers have been found to arise from sites of infection, chronic irritation, and inflammation. Inflammation orchestrates the microenvironment around tumors and allows them to progress by fostering proliferation, survival, and migration [149]. The inflammatory cells and the network of signaling molecules provided by the inflammatory microenvironment are necessary for the malignant progression of transformed cells.
Inflammation promotes tumor development through both nonimmune and immune. NF-κB is a central transcription factor mediating inflammatory and innate immune responses. NF-κB may be activated by various factors, including cytokines, microbial pathogens, and oxidative, genotoxic, physiological, or chemical stress factors. In addition to these, proinflammatory cytokines and chronic infections can play an important role in the stimulation of IKK activity, which leads to constitutive NF-κB activation [150,151,152]. The activation of NF-κB through IKKβ plays a major role in inflammation induced tumor promotion and progression. Various proinflammatory factors like TNFα and Toll-like receptor ligands such as lipopolysaccharide (LPS) normally activate these pathways [153]. This activation signals the transcription of various cancer-promoting genes such as antiapoptotic genes, proangiogenic genes, and proinvasion genes [154]. NF-κB DNA binding is thought to result in the activation of a number of genes that lead to inflammatory diseases like Alzheimer disease and arthritis in addition to cancer [143].
Along with NF-κB, factors such as TNF and interleukins (IL-1β, IL-6, and IL-8) also serve as connecting links between inflammation and cancer. TNF is released mainly from macrophages and regulates immune cells. Its dysregulation and overproduction lead to cancer and other diseases. TNF also plays a role in the activation of NF-κB by binding to a TNF receptor present on the cell surface that in turn triggers a pathway that leads to the activation of IKK [3]. Interleukins are a group of cytokines released in the body from numerous cells in response to various stimuli. While IL-1β plays an important role in the inflammatory response against infection by increasing the expression of endothelial adhesion factors, thus allowing infiltration of leukocytes at the site of infection, IL-6 is a proinflammatory cytokine released in response to trauma or tissue damage. IL-8, a member of the CXC chemokine family also known as CXCL8, can function as a mitogenic, angiogenic, and mutagenic factor promoting cancer progression [155].
Inflammatory cells and their regulators are found to facilitate angiogenesis and promote the growth, invasion, and metastasis of tumor cells [156]. Normal levels of some enzymes like inducible nitric oxide synthase (iNOS) and COX-2 play an essential role in the physiological protective response to tissue injury, but if expressed in excessive amounts, these inflammatory enzymes may cause carcinogenesis [149,157,158]. In tumor tissue, levels of prostaglandins (PGs) are often elevated. PGs are endogenous mediators of inflammation and are formed from arachidonic acid by constitutive COX-1 and inducible COX-2. Production of higher levels of PGs is thought to cause cellular injury and ultimately lead to carcinogenesis by inhibiting apoptosis, stimulating cellular proliferation, and promoting angiogenesis and tumor invasiveness [159]. Cycloartane triterpenoids from Cimicifuga dahurica suppressed the expression of cdc2 and COX-2 protein. These results imply that triterpenoids possess potential antitumor activities and exert their cytotoxicity through apoptosis and G2/M cell cycle arrest [146].
Many triterpenoids derived from botanical sources play an important role in reducing inflammation. These include avicin, asiatic acid, astragaloside, betulin, betulinic acid, boswellic acid, celastrol, cucurbitacin, diosgenin, erythrodiol, ganoderiol, ginsenosides, glycyrrhizin, glycyrrhetinic acid, gypenoside, lupeol, madecassic acid, maslinic acid, oleandrin, oleanolic acid, platycodon D, pristimerin, saikosaponins, ursolic acid, and withanolide (Table 2). Many of these triterpenoids target NF-κB, leading to its downregulation.
Pentacyclic triterpenoids have been found to have many functions, although their effective concentrations for various cellular effects may vary widely. Depending upon the dose administered, triterpenoids can induce anti-inflammatory, cytoprotective, tumor-differentiating, proliferation–arresting, and apoptotic effects [160,161,162]. The anticancer activities of triterpenoids appear to be mediated, at least in part, by their common ability to block TNF-induced NF-κB activation by inhibiting IKKβ [163,164]. The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole (CDDO-Im) blocks NF-κB activation through direct inhibition of IKKβ [35]. This is evident from the fact that the molecular targets of the synthetic oleanane triterpenoids include IKK and also pathways involving STAT, IL-6, TGF‑β, and KEAP1 (the inhibitor of the transcription factor Nrf2). Inhibition of multiple targets by triterpenoids is believed to be mediated by the promiscuous reversible Michael addition of these compounds to exposed nucleophilic groups (such as accessible cysteine sulfides) of various susceptible signaling proteins [165]. Triterpenoids affect multiple signaling pathways, and the clinical properties of triterpenoids, particularly those of pentacyclic triterpenoids, have been shown in various studies. The structure-activity relationships indicate that the presence of α,β-unsaturated carbonyl moieties significantly enhance the potency of these pentacyclic triterpenoids. Of the 12 pentacyclic triterpenoids, four (CDDO, CDDO-Me, pristimerin, and celastrol) have been shown to be potently and selectively lethal to different cancer cells and show a several fold increase in anti-inflammatory activity. This action is caused by the α,β-unsaturated carbonyl in ring A. The incorporation of a cyano and keto group within this enone moiety further enhances its efficacy and potency.
Avicins are electrophilic pentacyclic triterpenoids with proapoptotic, anti-inflammatory, and antioxidant properties derived from Acacia victoriae. Avicins have been shown to induce redox‑dependent post-translational modification of cysteine residues to regulate protein function, which downregulate both STAT3 activity and the expression of STAT3-regulated prosurvival proteins and contribute to the induction of apoptosis in vitro [166]. Avicins were found to be potent inhibitors of TNF-induced NF-κB and to slow the accumulation of the p65 subunit of NF-κB in the nucleus; however, the degradation of IκBα was unaffected. In addition Avicins blocked the binding of NF-κB to DNA in in vitro binding assays. Treatment of cells with dithiothreitol (DTT) totally reversed the avicin G-induced inhibition of NF-κB activity, suggesting that sulfhydryl groups critical for NF-κB activation were being affected. Avicin G treatment decreased the expression of NF-κB regulated proteins such as iNOS and COX-2 [16]. Other studies showed that pretreating cells with triterpenoids for 24 hours significantly reduced the induction of NF-κB mediated through TNF-α [44,167].
Pristimerin, a natural triterpenoid, elicits cellular responses closely resembling those elicited by proteasome inhibitors, such as the rapid induction of heat shock proteins (HSPs), activating transcription factor 3 (ATF3), and C/EBP homologous protein (CHOP). Pristimerin also inhibits NF‑κB activation by inhibiting IKK-α or IKK-β, whereas proteasome inhibitors instead suppress NF‑κB function by impairing the degradation of ubiquitinated IκB. By inhibiting both IKK and the proteasome, pristimerin suppresses the activation of constitutive NF-κB in myeloma cells. Multiple myeloma is exquisitely sensitive to proteasome or NF-κB pathway inhibition. Consistent with this, pristimerin has been shown to be potently and selectively lethal to primary myeloma cells (IC50 < 100 nM) and to inhibit xenografted plasmacytoma tumors in mice [118]. Pristimerin is also known as an antifungal, antimicrobial, and anti-inflammatory plant compound with an effect on the iNOS system in LPS-activated RAW 264.7 macrophages [168].
Celastrol, a natural triterpenoid with a structure similar to that of pristimerin, is found in the thunder god vine and was identified as having potential for use in cancer treatment because of its ability to enhance the death of melanoma cells. Celastrol also inhibited cell proliferation in melanoma cells. When celastrol was used to treat melanoma cells, it (like pristimerin) increased levels of ubiquitinated proteins, reduced levels of TNF-α-induced IκB phosphorylation, and blocked NF-κB translocation to the nucleus at nanomolar concentrations; however, the molecular mechanism for these effects differed. Celastrol normally inhibits LPS-induced phosphorylation of mitogen-activated protein kinases/extracellular signal-regulated kinases 1/2 (MAPK/ERK1/2) and the DNA binding activity of NF-κB [49]. Other studies have indicated that TNF-induced IKK activation requires the activation of TAK1 and that celastrol inhibits the TAK1-induced NF-κB activation [52]. Celastrol also suppressed the ovalbumin-induced airway inflammation, hyperresponsiveness, and tissue remodeling by regulating the imbalance of matrix metalloproteinase 2 and 9 (MMP2, MMP9) and tissue inhibitor of metalloproteinase 1 and 2 (TIMP1 and TIMP2) by inflammatory cytokines through MAP kinases and NF-κB in inflammatory cells.
The triterpenoids erythrodiol and madecassic acid are structural analogues of each other and have antiproliferative and anticancer activity. However, only madecassic acid has also shown LPS‑stimulated NF-κB inhibition with subsequent blocking of p65 protein translocation to the nucleus [103]. This may be because of the presence of an additional hydroxyl at carbon 2, which play an important role in the electrophilic reaction. Maslinic acid, which is similar to madecassic acid, also inhibits NF-κB translocation. Maslinic acid also inhibited p50, p65, and NF-κB translocation in a dose-dependent manner in both unstimulated and phorbol-myristate acetate (PMA)-challenged cells, being particularly effective on the p50 subunit [169]. Momordin, an analogue of maslinic acid, does not contain any hydroxyl group at the carbon 2 position but still it has shown NF-κB inhibition in osteoclast differentiation. This may be because of momordin’s action on c-Fos, a component of the activating protein-1 (AP-1) transcription factor that plays a key role in osteoclast differentiation. Momordin inhibited the activation of NF-κB as well as AP-1 in receptor activator of NF-κB ligand (RANKL)-induced RAW264.7 cells, in which momordin appeared to target IκB degradation and c-Fos expression, but not MAPK signaling pathways [104].
Saikosaponins are triterpene saponins derived from the medicinal plant Bupleurum falcatum L. (Umbelliferae) that have shown various pharmacological and immunomodulatory activities including anti-inflammatory, antibacterial, antiviral and anticancer effects in ACHN, C32, Caco-2 , A375, A549, and Huh-7D12 cell lines [170]. Studies demonstrated that saikosaponins not only suppressed the proliferation of human T cells costimulated with OKT3 and CD28 but also inhibited PMA-, PMA/ionomycin-, and concanavalin A-induced mouse T-cell activation in vitro. This inhibitory effect of saikosaponins on PMA-induced T-cell activation was associated with the downregulation of NF-κB signaling through the suppression of IKK and Akt activities. Saikosaponins also suppressed both the DNA binding activity and the nuclear translocation of nuclear factor of activated T cells (NF-AT) and AP-1 in the PMA/ionomycin-stimulated T cells. In addition, the cell surface markers like IL-2 receptor (CD25) were also downregulated, and the production of proinflammatory cytokines such as IL-6, TNF-α, and interferon (IFN)-γ was decreased. These results indicate that the NF-κB, NF-AT, and AP‑1 (c-Fos) signaling pathways are involved in the T cell inhibition evoked by saikosaponins, demonstrating their potential for treating T cell-mediated autoimmune conditions [123]. Another study showed that saikosaponins have direct involvement in p53-, NF-κB- and Fas/Fas ligand-mediated induction of apoptosis and cell cycle arrest in human hepatoma cell lines. Saikosaponins also inhibited cell survival signaling by enhancing the amount of IκBα in the cytoplasm and reducing the level and activity of NF-κB in the nucleus, and subsequently attenuated the expression of bcl-xL in HepG2 and Hep3B cells. Saikosaponins therefore decreased cell proliferation and induced apoptosis both in p53‑positive HepG2 and p53-negative Hep3B cells [121].
Diosgenin, a steroidal triterpenoid having two pentacyclic rings, is present in Trigonella foenum graecum and other plants and has been shown to suppress inflammation, inhibit proliferation, and induce apoptosis in a variety of tumor cells. Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, IKK activation, and NF-κB-regulated gene expression. Diosgenin suppresses NF-κB through direct DNA binding, activation of IKK, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, and p65 nuclear translocation by inhibiting Akt activation. NF-κB-dependent reporter gene expression was also abrogated by diosgenin [64]. Similar activity was found in Withania somnifera, also known as Indian ginseng, which is widely used in the Ayurvedic system of medicine to treat tumors, inflammation, arthritis, asthma, and hypertension. Chemical investigation of the roots and leaves of this plant has yielded bioactive withanolides, a group of C28-steroidal lactone triterpenoids. Withania somnifera inhibits COX enzymes, lipid peroxidation, and proliferation of tumor cells, and it potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis through the suppression of NF-κB activation and NF-κB-regulated gene expression [135].
Ursolic acid is a pentacyclic triterpene compound isolated from many types of medicinal plants and widely present in the human diet. It has been reported to possess a wide range of pharmacological properties and is one of the most promising chemopreventive agents for cancer. It has been shown to suppress the expression of several genes associated with tumorigenesis. It suppressed NF-κB activation induced by various carcinogens including TNF, PMA, okadaic acid, hydrogen peroxide (H2O2), and cigarette smoke condensate. Ursolic acid inhibited DNA binding of NF-κB. Ursolic acid inhibited IκBα degradation, IκBα phosphorylation, IKK activation, p65 phosphorylation, p65 nuclear translocation, and NF-κB-dependent reporter gene expression. Ursolic acid also inhibited NF-κB-dependent reporter gene expression activated by TNF receptor (TNFR), TNFR-associated death domain (TRADD), TNFR-associated factor (TRAF), NF-κB-inducing kinase (NIK), IKK, and p65 [125]. CDDO and CDDO-Me, two potent oleanane triterpenoids having structures similar to ursolic acid, are currently in Phase I clinical trials for the treatment of leukemia and solid tumors. CDDO blocks the action of NF-κB by preventing the nuclear translocation of p65; this blocks the transactivation of the NOS2 and PTGS2 genes, thus playing an anti-inflammatory role and causing cell cycle arrest. Cucurbitacin combined with CDDO has been shown to bring about apoptosis by inhibiting NF-κB activation, IκBα phosphorylation and degradation, NF-κB-reporter gene expression induced by TNF, and STAT signaling. Some other triterpenoids like astragaloside, boswellic acids, celastrol, ganoderiol F, and gypenoside also blocked the action of NF-κB, inhibiting the transactivation of cox-2 [44,51,171,172,173]. CDDO, at nanomolar concentrations, suppresses the de novo synthesis of the inflammatory enzymes iNOS and COX-2 in activated macrophages because they contain α,β‑unsaturated carbonyl moieties. Since iNOS and COX-2 overexpression have been implicated as possible enhancers of carcinogenesis, CDDO has potential to be used as a chemopreventive agent. Furthermore, CDDO may also serve as a chemotherapeutic agent, as micromolar to nanomolar concentrations effectively induced differentiation of human myeloid leukemia cells, inhibited the proliferation of various human tumor cell types, and induced apoptosis in human myeloid and lymphocytic leukemia cells, osteosarcoma cells, and breast cancer cells, including cell lines resistant to chemotherapy [160].
Boswellic acids, a type of pentacyclic triterpenoid, have been shown to induce apoptosis in different cancer cells. At the molecular level, these compounds inhibit constitutively activated NF-κB signaling by intercepting the IKK activity; signaling through the IFN-stimulated response element remained unaffected, suggesting specificity for IKK inhibition [45,46]. In a xenograph study of animal meningioma cells, boswellic acids were found to have potent cytotoxic activity with IC50 values in the range of 2–8 μM. At low micromolar concentrations, boswellic acids rapidly and potently inhibited the phosphorylation of ERK-1/2 and impaired the motility of meningioma cells stimulated with platelet derived growth factor (PDGF) BB. The cytotoxic action of boswellic acids on meningioma cells may be mediated, at least in part, by the inhibition of the ERK signal transduction pathway, which plays an important role in signal transduction and tumorigenesis [174].
Platycodon, a triterpenoid isolated from Platycodon grandiflorum, showed chemopreventive effects on tumor invasion and migration in HT-1080 tumor cells. Platycodon reduced PMA-enhanced MMP9 and MMP2 activation in a dose dependent manner. Platycodon suppressed PMA enhanced expression of MMP9 protein as well as mRNA and transcription activity levels through the suppression of NF-κB activation without changing the TIMP1 levels. Platycodon also reduced PMA-enhanced expression of MMP2 active forms through the suppression of membrane-type 1 MMP (MT1-MMP), but platycodon did not alter MMP2 and TIMP2 levels. Moreover, ROS production induced by PMA was partly decreased in the presence of platycodon, and this suppression of ROS production may be related to diminished NF-κB activity [175]. In this case, NF-κB inhibition is totally ROS mediated, and most of these ROS are released from glucose molecules that are present on the side chain. Platycodon has been shown to be cytotoxic and to inhibit telomerase activity by downregulating hTERT expression at concentrations between 10 and 20 μM. Platycodon also reduced c-Myc and SP1 protein levels and DNA binding activities in a dose-dependent manner [176] and suppressed the LPS-induced expression of iNOS and COX-2 genes by suppressing NF-κB activation at the transcriptional level [51]. Platycodon also enhanced the mRNA expression of cytokines IL-2, IFN-γ, IL-4, and IL-10 and transcription factors T‑bet and GATA-3 in mice splenocyte induced by concanavalin A. This suggests that the number of sugar residues in the glycosidic chains attached to C-3 of aglycone could affect the hemolytic and adjuvant activities of platycodigenin-type saponins [177]. Betulinic acid suppressed NF-κB-dependent reporter gene expression and the production of NF-κB-regulated gene products such as COX-2 and MMP9, which are induced by inflammatory stimuli. It also suppressed TNF-induced apoptosis through the activation of NF-κB and NF-κB-regulated gene expression induced by carcinogens and inflammatory stimuli [35].

4.2. Role of Triterpenoids in Tumor Cell Survival, Apoptosis, and Proliferation

Apoptosis, which in Greek literally means “falling away,” is a process of programmed cell death that occurs normally in multicellular organisms. Apoptosis is a natural, organized process that plays an important role in embryonic development and adult tissue equilibrium by adjusting the physiological processes involved. The human body is made up of six trillion cells, with approximately three billion cells replaced every minute. Through the process of apoptosis, the body can eliminate damaged or unneeded cells without local inflammation from the leakage of cell contents [178].
Because deregulation of apoptosis is one of the most important factors involved in tumor cell progression, a number of scientific studies have been done on this process to determine if it can be exploited in cancer treatment. Apoptosis is the human body’s mechanism for destroying any cell that has abnormalities such as DNA damage, oncogene activation, nutrient deficiency, or hypoxia. But cancer cells have the ability to escape apoptosis, allowing tumors to grow rapidly and uncontrollably.
Apoptosis in cancer cells can be triggered by the activation of proteases such as caspases, leading to the cells’ destruction. There are two different pathways by which this apoptosis can be stimulated in cancer cells. The first is the intrinsic pathway through mitochondria, which releases cytochrome C proteins such as second mitochondria derived activator of caspases (SMACs) that bind to and deactivate inhibitor of apoptosis proteins (IAPs), allowing apoptosis to proceed. Apoptotic signals in this pathway may come in the form of members of the Bcl-2 family of proteins such as pro-apoptotic Bax, which can be upregulated by tumor suppressor protein p53 in response to DNA damage [179]. The second pathway is the extrinsic pathway, in which apoptosis is triggered by the activation of proapoptotic receptors such as death receptors 4 and 5 (DR4 and DR5) and Fas, which are present on the cell surface. The activation of the death receptor pathway leads to receptor aggregation, which then initiates the recruitment and activation of initiator caspase-8. While p53 is involved in the intrinsic pathway, it has no role in the extrinsic pathway [178,180,181,182].
STAT3 activation has been associated with cell survival, proliferation, and invasion in various human cancers. Some members of the Bcl-2 family of proteins, such as Bcl-2 and Bcl-xL, also play a role in apoptosis and have been found to be elevated in different types of cancer cells. These proteins cause some cells to develop resistance to drugs used in cancer treatment. Another protein, survivin, may play a role in tumor progression as it has been found at excessive levels in cancer cells. Targets for the treatment of cancer could be those that cause downregulation of the Bcl-2, Bcl-xL, and survivin proteins and upregulation of the p53, Bax, and caspase proteins.
Triterpenoids have been found to act through the intrinsic apoptosis pathway to prevent tumor progression. For example, many spice derived triterpenoids have been shown to induce apoptosis in different types of cancer cells through a wide variety of mechanisms. Among the most important of these are asiatic acid, astragaloside, celastrol, cucurbitacin, diosgenin, gypenoside, hederagenin, lupeol, and momordin (Table 2). These triterpenoids have a common target, the antiapoptotic protein Bcl-2, which can induce apoptosis in cancer cells.
Pristimerin has been shown to induce mitochondrial cell death in human cancer cells, and the ROS dependent activation of both Bax and poly (ADP-ribose) polymerase-1 (PARP-1) is critically required for mitochondrial dysfunction [117,183]. In human HL-60 cells, pristimerin also showed antiproliferative effects, with an IC50 of 0.88 μM [184]. In addition to this, pristimerin showed that c‑Jun N-terminal kinase (JNK) was involved in ROS-dependent Bax activation, which increases intracellular ROS, JNK activation, conformational change, and mitochondrial redistribution of Bax, mitochondrial membrane potential loss, and cell death. Pretreatment with pristimerin also activated PARP-1 [117]. Another study showed that pristimerin induced apoptosis by targeting the proteasome in prostate cancer cells. This may be because of the accumulation of ubiquitinated proteins and three proteasome target proteins, Bax, p27 and IκBα, in androgen receptor (AR)-negative PC-3 prostate cancer cells, which supports the conclusion that proteasome is inhibited by pristimerin [120]. Another study showed that this apoptosis might be induced by pristimerin through the direct effect of caspase on mitochondria in MDA-MB-231 cells [119]. Pristimerin showed antiviral activity by inhibiting the viral DNA synthesis but had no virucidal effect [185].
Celastrol combined with TNF-related apoptosis-inducing ligand (TRAIL/APO-2L) exerted strong synergistic antiproliferative effect against human cancer cells, including those from ovary cancer (OVCAR-8), colon cancer (SW620), and lung cancer (95-D). In vivo, the antitumor efficacy of TRAIL/APO-2L was dramatically increased by celastrol. These enhanced anticancer activities were accompanied by the prompt onset of caspase-mediated apoptosis. Celastrol also suppressed the TNF‑induced expression of various gene products involved in antiapoptosis (IAP1, IAP2, Bcl-2, Bcl‑xL, c-FLIP, and survivin), proliferation (cyclin D1 and COX-2), invasion (MMP9), and angiogenesis (VEGF) [52].
Diosgenin-induced apoptosis was associated with COX-2 upregulation in HEL cells [75]. Diosgenin also downregulated gene products involved in cell proliferation (cyclin D1, COX-2, and c‑myc) and antiapoptosis (IAP1, Bcl-2, Bcl-xL, Bfl-1/A1, TRAF1, and cFLIP) [64].
Avicins are novel plant derived metabolites that lower energy metabolism in tumor cells by targeting the outer mitochondrial membrane Avicins dephosphorylated STAT3 in a variety of human tumor cell lines, leading to a decrease in the transcriptional activity of STAT3. The expression of STAT3-regulated proteins such as c-myc, cyclin D1, Bcl-2, survivin, and VEGF were reduced in response to avicin treatment. Avicin also induced dephosphorylation of STAT3, dephosphorylation of JAKs, and activation of protein phosphatase-1 [11]. Another study showed that avicins induced apoptosis and downregulated p-STAT3, Bcl-2, and survivin in cutaneous T-cell lymphoma cells. Avicin D did not change STAT3 expression, but it decreased phospho-STAT3 protein levels [13,187].
Betulinic acid inhibited the constitutive activation of STAT3, Src kinase, JAK1, and JAK2. Pervanadate reversed the betulinic acid induced down regulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase (PTP). Betulinic acid also downregulated the expression of STAT3 regulated gene products, such as Bcl-xL, Bcl-2, cyclin D1, and survivin. This correlated with an increase in apoptosis as indicated by an increase in the sub-G1 cell population and an increase in caspase-3-induced PARP cleavage [188].
Recently, some researchers found that natural triterpenic diols promote apoptosis in astrocytoma cells through ROS-mediated mitochondrial depolarization and JNK activation. Alcohols extracted from olive oil, erythrodiol (an intermediate from oleanolic acid), and its isomer, uvaol, have been reported anticancerous, particularly on brain cancer cells. Erythrodiol and uvaol effectively affected cell proliferation as well as cell cycle phases and induced 1321N1 cell death and modulated the apoptotic response, promoting nuclear condensation and fragmentation. These results may be due to production of ROS with loss of mitochondrial transmembrane potential, and correlated with the activation of JNK. The presence of catalase reversed the triterpenic diols induced mitochondrial depolarization, JNK activation, and apoptotic death, indicating the critical role of ROS in the action of diols ring compounds [189]. Oleanolic acid also upregulated COX-2 expression and induced prostacyclin (PGI2) synthesis. These effects may be as a result of the early activation of cAMP regulatory element-binding protein (CREB), a key transcription factor involved in COX-2 transcriptional upregulation. Oleanolic acid has also shown cardioprotective effects [190].
Maslinic acid is present in high concentrations in olive pomace. Various studies have examined the responses of HT-29 and Caco-2 colon cancer cell lines to maslinic acid treatment. It also induced strong G0/G1 cell-cycle arrest and DNA fragmentation, and increased caspase-3 activity. However, maslinic acid did not alter the cell cycle or induce apoptosis in the non-tumorous intestinal cell lines IEC-6 and IEC-18 [191].
Momordin inhibited proliferation and induced apoptosis in human promyelocytic leukemia (HL-60) cells and was cytotoxic to HL-60 cells with an IC50 of 19.0 μg/mL. The antiproliferative effects of momordin appear to be attributable to its induction of apoptotic cell death, as momordin induced nuclear morphology changes and internucleosomal DNA fragmentation and increased the proportion of hypodiploid cells. Momordin decreased the expression of the antiapoptotic protein Bcl-2 but increased the expression of the proapoptotic protein Bax. In addition, treatment with momordin induced the activation of caspase-3 and the cleavage of PARP [105]. Many of the triterpenoids derived from nature, target caspases, which are essential for apoptotic cell death.
Saikosaponins were found to be cytotoxic in different cancer cell lines and to exert significant inhibition of nitric oxide production in LPS-induced RAW 264.7 macrophages, with IC50 of 4.2 and 10.4 μM, respectively [170]. Saikosaponins have shown a variety of pharmacological and immunomodulatory activities, including anti-inflammatory, antibacterial, antiviral and anticancer effects. Treatment of MDA-MB-231 with saikosaponin-A increased the population of cells in the sub‑G1 phases of the cell cycle. These results showed that apoptosis in MDA-MB-231 cells was independent of the p53/p21 pathway mechanism and was accompanied by an increased ratio of Bax to Bcl-2, increased c-myc levels, and increased activation of caspase-3. In contrast, apoptosis of MCF7 cells may have been initiated by the Bcl-2 family of proteins and involved the p53/p21-dependent pathway mechanism, and it was accompanied by an increased level of c-myc protein [192]. In another study, an enhancement in Fas and its two ligands, membrane-bound Fas ligand (mFasL) and soluble Fas ligand (sFasL), as well as Bax protein, was shown to be responsible for the apoptotic effect induced by saikosaponins [121]. Saikosaponins significantly increased the levels of c-myc and p53 mRNA [193]. Saikosaponins also caused G0/G1 cell cycle arrest of activated T cells by downregulating the protein levels of CDK6 and cyclin D3 and upregulating the protein level of p27(kip) [194].
The inhibition of NF-κB activation by ursolic acid correlated with the suppression of NF-κB dependent cyclin D1, COX-2, and MMP9 expression [125]. Ursolic acid blocked cell cycle progression in the G1 phase and was associated with a marked decrease in the protein expression of cyclin D1, D2, and E, and their activating partners cdk2, cdk4, and cdk6 with concomitant induction of p21. The accumulation of p21/WAF1 might be p53 dependent. The accumulation of p21/WAF1 correlated with the upregulation of Fas, the Fas ligands and Bax, and the downregulation of NF-κB, Bcl-2, and Bcl-xL [121]. Ursolic acid also upregulated apoptotic genes p53 and caspase-3, while the antiapoptotic gene Bcl-2 was downregulated [124].
CDDO, concentrated at 1–5 μM, induced apoptosis in various cancer cell lines. Moreover, CDDO combined with TRAIL promoted the induction of apoptosis. CDDO normally acts through both the extrinsic and intrinsic pathways by activating the cleavage of BID and of caspases-3, -8, and -9; by downregulating FLIP; or by inducing the translocation of Bax to the mitochondria and the release of cytochrome C [195,196,197]. The antitumor activity of CDDO-Me was associated with the inhibition of p-Akt, mammalian target of rapamycin (mTOR), and NF-κB signaling proteins and their downstream targets such as p-Bad and p-Foxo3a for Akt; p-S6K1, p-eIF-4E and p-4E-BP1 for mTOR; and COX-2, VEGF and cyclin D1 for NF-κB [167].
Acetyl-11-keto-β-boswellic acid (AKBA), a derivative of boswellic acid has been shown to induce apoptosis in cancer cells. AKBA mediated inhibition of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway; this pathway is crucial for cell proliferation and survival [198]. Another study showed that cyclin D1 and E, CDK2 and 4 and phosphorylated retinoblastoma protein (Rb) were decreased in AKBA-treated cells, while p21expression was increased. The growth inhibitory effect of AKBA was dependent on p21 but not p53 [199]. The cytostatic and apoptosis inducing activities of boswellic acids toward malignant cell lines has been shown in vitro [200]. Boswellic acids triggered apoptosis by means of a pathway dependent on caspase-8 activation but independent of Fas/Fas ligand interaction in colon cancer cells [201]. AKBA inhibited the NF-κB-dependent reporter gene expression activated by TNFR, TRADD, TRAF2, NIK, and IKK, but not that activated by the p65 subunit of NF-κB, which indicates that AKBA enhances apoptosis induced by cytokines and chemotherapeutic agents [46].
In HT-29 human colon cancer cells, platycodon induced apoptosis through DNA fragmentation and PARP cleavage. The apoptosis induced by platycodon was associated with the activation of initiator caspases-8 and -9 as well as effector caspase-3. Platycodon stimulated Bid cleavage, indicating that the apoptotic action of caspase-8-mediated Bid cleavage leads to the activation of caspase-9. It increased the expression of the proapoptotic protein Bax and decreased the expression of the antiapoptotic protein Bcl-2. Platycodon also increased the expression of the caspase-independent mitochondrial apoptosis factor, apoptosis inducing factor (AIF), in HT-29 cells. Thus, platycodon exerts its apoptotic effect via both caspase-dependent and caspase-independent pathways [116,202,203].
A few triterpenoid compounds have been shown to both activate caspase activity and downregulate the expression of Bcl-2 or Bcl-xL. The ability to suppress proliferation and induce apoptosis in human cancer cells is clearly important for drugs targeting either malignant cells in treatment or premalignant cells in prevention.
One of the hallmarks of cancer is aggressive proliferation of cells. In a normal cell, a fine balance between growth signals and antigrowth signals regulates proliferation. However, this fine orchestration is lost in cancer cells, which often show uncontrolled growth due to the loss of both growth-controlling factors. On one hand, cancer cells acquire the capability to generate their own growth signals, while on the other hand, they also become unresponsive to antigrowth signals [204]. Numerous factors regulate the natural progression of a normal cell. Some of these factors, such as cyclins, are upregulated in cancer cells, causing the cells to replicate uncontrollably. Cyclins are the regulatory proteins that control the cell cycle, while other factors such as COX-2 and c-myc play a supporting role. The most commonly affected cyclin in cancer cells is cyclin D1, an important cell cycle regulator that plays a role in transition of the cell from the G1 phase to the S phase. Cancer cells show overexpression of this cyclin D1 and thus it has been linked to the development and progression of cancer.
Avicins downregulate both STAT3 and the expression of STAT3-regulated prosurvival proteins, which contribute to the induction of apoptosis in tumor cells. STAT3 plays an important role in inflammation and wounding, and the in vivo inhibition of VEGF. In a mouse skin carcinogenesis model, avicins inhibited the expression of STAT3, resulting in the suppression of the pro-inflammatory and pro-oxidant stromal environment of tumors [11]. Avicins at concentrations of 0.5–5.0 μg/mL caused more apoptosis in patients' Sézary cells than in healthy donors' CD4+ T cells and activated CD4+ T cells and decreased apoptosis inhibitors bcl-2 and survivin [13]. Furthermore, avicin D-induced autophagic cell death was abrogated by knockdown of tuberous sclerosis complex 2 (TSC2), a key mediator linking AMP-activated protein kinase (AMPK) to mTOR inhibition, suggesting that AMPK activation is a crucial event targeted by avicins. Avicins also have been shown to lower energy of metabolism in tumor cells by targeting the outer mitochondrial membrane, causing cancer cell death [187]. Tumor cells generate hydroperoxides at a very high rate, and avicins could provide a new strategy of anticancer therapy by sensitizing cells with high levels of ROS to apoptosis. In another study, boswellic acids, which inhibit STAT3 activation, led to the suppression of gene products involved in proliferation (cyclin D1), survival (Bcl-2, Bcl-xL, and Mcl-1), and angiogenesis (VEGF) [32].
Maslinic acid has shown an antiproliferative effect against Caco-2 cancer cells (EC50 = 15 µM), HT-29 human colon cancer cells (EC50 = 74 µM), 1321N1 astrocytoma cells (EC50 = 25 µM), and human leukemia cells (CCRF-CEM and CEM/ADR5000) (EC50 = 7 and 9 µM, respectively). Maslinic acid’s antiproliferative activity likely comes from the induction of an oxidative apoptotic pathway, which causes cell cycle and cytoskeleton alterations. Maslinic acid has been found to attenuate intracellular oxidative stress by inhibiting of NO and H2O2 production and reducing proinflammatory cytokine generation in murine macrophages [205]. Maslinic acid inhibited cell growth with an EC50 of 101.2 μM without necrotic effects. This effect of maslinic acid is caused by a hydroxyl group at the carbon 2 position, ultimately activates caspase-3 as a prime apoptosis protease [206]. A 200 μM concentration of maslinic acid was sufficient for activating caspase-3, which inhibits cell proliferation [207]. Maslinic acid from pomace olive oil demonstrated a suppressive effect on oxidative stress and cytokine production in stimulated murine macrophages [208]. Triterpenoids isolated from apple peels have shown potent antiproliferative activity and may be partially responsible for apples’ anticancer activity.
Saikosaponins prevented the proliferation of MCF-7 cell at the concentration of 10 nM to 10 μM and was significantly inhibited by the specific estrogen receptor (ER) antagonist ICI-182780 [209]. This antiproliferative effect is due to the synthesis of extracellular matrix proteins through the downregulation of the CDK4, c-Jun, and c-Fos genes [210], which block cell cycle progression at the G1 phase.
The potency of ursolic acid was associated with ZIP/p62 and protein kinase C-zeta (PKC-zeta). Ursolic acid inhibited the interaction of ZIP/p62 and PKC-zeta. It also further suppressed the activation of NF-κB and the downregulation of the MMP9 protein, which in turn contributed to ursolic acid’s inhibitory effects on IL-1β or TNF-induced C6 glioma cell invasion [127]. Ursolic acid showed the strongest inhibitory activity to urokinase (IC50 = 12 μM) and cathepsin B (IC50 = 10 μM), and as proteases are involved in tumor invasion and metastasis, this activity could be beneficial in cancer treatment [211]. CDDO-Me inhibited growth and induced apoptosis in PC-3 and C4-2 cells and was associated with the inhibition of the p-Akt, mTOR, and NF-κB signaling proteins and COX-2, VEGF and cyclin D1 [167]. Some of the triterpenoid derivatives obtained from ursolic acid have shown ability to suppress the de novo formation of two enzymes, iNOS and COX-2, in IFN-γ-stimulated primary mouse macrophages or LPS-activated RAW 264.7 macrophages that are used as assay systems [212].
The inhibition of STAT3 activation by boswellic acids led to the suppression of gene products involved in proliferation (cyclin D1), survival (Bcl-2, Bcl-xL, and Mcl-1), and angiogenesis (VEGF. Betulinic acid combined with vincristine showed a synergistic cytotoxic effect on melanoma cells, inducing cell cycle arrest at different points (betulinic acid at G1 phase and vincristine at G2/M phase) and causing apoptosis in B16F10 melanoma cells. In C57BL/6 mice, vincristine inhibited metastasis of melanoma cells to the lung, an effect that was augmented by the addition of betulinic acid [213].

4.3. Role of Triterpenoids in Invasion, Metastasis, and Angiogenesis

Besides uncontrolled proliferation, the other major characteristics of cancer cells are invasion and metastasis. In metastasis the cancer cells migrate from their original site of origin to other parts of the body, either via the bloodstream or lymphatic system. Among the factors influencing invasion, which affects whether or not a tumor will metastasize, are MMPs and ICAM-1. MMPs (specifically MMP2 and MMP9) are endopeptidases that degrade the basement membrane components, separating the cells from their surrounding tissue and enabling them to move freely and spread to other tissues [214]. Chemokine receptor CCR7 is important for lymphatic invasion of cancer cells and is overexpressed in metastatic breast cancer cells; withanolide inhibits TAK1 to repress NF-κB-induced CCR7 expression in breast cancer cells and is useful for the prevention of lymphatic involvement by breast cancer cells [215].
Erythrodiol-3-acetate, a triterpenoid, reduced the level of MMP1 and induced type 1 procollagen in a dose dependent manner [216]. Ganoderma lucidum, a well known mushroom containing platycodon, showed a significant inhibitory effect on PMA-induced MMP9 and MMP2 activation in a dose dependent manner and further inhibited HT-1080 and HepG2 cell invasion and migration [217]. Another study found that boswellic acids potentiated the apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced invasion, and inhibited NF-κB-induced osteoclastogenesis [46].
Angiogenesis is the basis for solid tumor development and distribution, and antiangiogenic drugs have been demonstrated to be active at the site of cancer. The growth of human tumors and development of metastases depends on the de novo formation of blood vessels [218]. Angiogenesis, the physiological process in which new blood vessels develop from pre-existing ones, normally occurs during growth, reproduction, and wound healing; however, this process is also a marker indicating that a tumor has progressed from a dormant to malignant state. Angiogenesis favors tumor growth by providing oxygen and nutrients to multiplying cells via the newly formed blood vessels. Some proangiogenic factors that favor development of new blood vessels include IL-8, TNF, fibroblast growth factor-2 (FGF-2), and PDGF. However, the most important factor in the whole process of angiogenesis is VEGF. Various studies have shown it to be a potent stimulator of angiogenesis in vitro [218]. Because of its critical role in angiogenesis, it has been targeted for controlling tumor progression. Limiting VEGF in tumors has been shown to lead to blood vessel destruction and to prevent the growth of new ones, thus reducing the blood supply to the tumor. Inhibition of the VEGF tyrosine kinase signaling pathway blocked angiogenesis in growing tumors, leading to stasis and regression of the tumors. Thus, agents that can downregulate or inhibit the expression of VEGF or its signaling pathway in tumor cells could prove to be very promising in preventing tumor growth and metastasis.
Saikosaponin C, one of the saikosaponins present in a Chinese herb, Radix bupleuri, has been found to have a potent inducing effect on human umbilical vein endothelial cells’ viability and growth. Saikosaponin C also induced endothelial cell migration and capillary tube formation. Saikosaponin C induced the gene expression or activation of MMP2, VEGF, and the p42/p44 MAPK that correlates with endothelial cell growth, migration, and angiogenesis, respectively [219]. Another study found that saikosaponins can inhibit the physiological angiogenesis of chicken embryos, especially for the medium and small vessels [220].
CDDO-Me and CDDO-Im were shown to inhibit the activation of the ERK1/2 pathway after stimulation with VEGF in human umbilical vein endothelial cells [221]. CDDO-Me also potentiated the cytotoxic effects of TNF and chemotherapeutic agents. This may be because CDDO-Me inhibits NF-κB through the inhibition of IκBα kinase, leading to the suppression of NF-κB-regulated gene product (VEGF, COX-2, and MMP9) expression and to angiogenesis [222]. Boswellic acids suppressed VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2) kinase (KDR/Flk-1) with an IC50 of 1.68 μM. Specifically, boswellic acids suppressed the downstream protein kinases of VEGFR2, including Src family kinase, focal adhesion kinase, ERK, AKT, mTOR, and ribosomal protein S6 kinase [223]. In an ex vivo model, boswellic acids significantly inhibited blood vessel formation in the Matrigel plug assay in mice and effectively suppressed VEGF induced microvessel sprouting in a rat aortic ring assay. Furthermore, boswellic acids inhibited VEGF induced cell proliferation, chemotactic motility, and the formation of capillary-like structures from primary cultured human umbilical vascular endothelial cells in a dose-dependent manner [223]. Betulinic acid also inhibits growth factor-induced in vitro angiogenesis by modulating mitochondrial function in endothelial cells [224].
Various in vivo studies have found that celastrol can downregulate the density of tumor microvessels significantly at different doses. Immunohistochemistry showed that celastrol also decreased the levels of VEGFR1 and VEGFR2 expression, but not the level of VEGF expression [225]. However, avicins, downregulate the expression of VEGF [166]. An in vivo study showed that Ganoderma lucidum given at 100 and 200 mg/kg inhibited primary solid tumor growth in the spleen, liver metastasis, and secondary metastatic tumor growth in the liver in intrasplenic Lewis lung carcinoma-implanted mice. An in vivo assay system extract inhibited Matrigel induced angiogenesis [226].

5. Role of Triterpenoids in Cancer Treatment

Triterpenoids are structurally diverse organic compounds. More than 20,000 triterpenoid varieties are formed by multiple modifications of the basic backbone structure. Several triterpenoids such as avicin, betulinic acid, boswellic acids, celastrol, diosgenin, madecassic acid, maslinic acid, momordin, saikosaponins, platycodon, pristimerin, ursolic acid, CDDO, and withanolide, have been shown in our laboratory and others to possess anticancer and anti-inflammatory activities. Preliminary data from ongoing studies indicate that some synthetic triterpenoids are being developed with improved anticancer activity. Several triterpenoids are now in clinical trials at different phases (Table 4; www.clinicaltrials.gov). Synthetic triterpenoid, CDDO, is being tested in patients with various cancers. Betulinic acid ointment is under evaluation for the treatment of dysplastic nevi that have the potential to transform into melanoma. Triterpenoids are highly multifunctional and thus have promise as agents in the treatment of cancer because of their ability to block the NF-κB activation, induce apoptosis, and inhibit proliferation, invasion, metastasis and angiogenesis.
Table 4. List of triterpenoids in clinical trials.
Table 4. List of triterpenoids in clinical trials.
Triterpenoids CancerPhaseStatusSponsors
CDDO-MeSolid tumors or ITerminated MDACC
Lymphoid malignancies
CDDOSolid TumorsICompletedNCI
or Lymphoma
CDDO-MeLiver diseaseI/IITerminatedRPI
GinsenosideBreast cancerIIOngoingSIU
GinsenosideHypertensionIICompletedSMH
Ginsenoside Ischemic StrokeII/IIICompletedXH
Betulinic acid Dysplastic nervus syndromeI/IIOngoingUI
EscinArm lymphedemaIICompletedUW
GlycyrrhizinHepatitis CIIIOngoingSP
Glycyrrhetinic acid End stage renal diseaseIIOngoingUHI
Glycyrrhetinic acid AMEII/IIICompletedBWH
MDACC, MD Anderson Cancer Center, U.S.; NCI, National Cancer Institute, U.S.; RPI, Reata Pharmaceuticals, Inc; SIU, Southern Illinois University; SMH, St. Michael's Hospital, Toronto; XH, Xijing Hospital, China; UI, University of Illinois; UW, University of Wisconsin, U.S.; SP, Schering-Plough; UHI, University Hospital Inselspital, Switzerland; AME, Apparent Mineralocorticoid Excess; BWH, Brigham and Women's Hospital, U.S.

6. Conclusions

This review has illustrated that triterpenoids are important active constituents obtained from various plants and could be considered for use in both the chemoprevention and chemotherapy of cancer. Inflammatory proteins and their pathways are critical targets in both the prevention and treatment of cancer. Therefore, identification of agents or drugs that can suppress these pathways is of enormous importance.
Polycyclic triterpenoids now offer important new platforms for drug development. The natural triterpenoid platform provided by the unique stereochemistry of these particular compounds, and the cyclization of the linear 30-carbon squalene molecule, have provided an excellent base from which new agents more potent than the parent squalene could be developed.
Thus, agents that can suppress NF-κB and activate caspase and other pathways (e.g., DR4, DR5) are likely to be effective drugs. Because of their safety and ability to affect multiple targets, natural products are likely to have a special place in the preventive and therapeutic armamentarium against cancer. Although there are extensive preclinical data to support such claims, only clinical studies can fully validate them.

References

  1. Balunas, M.J.; Kinghorn, A.D. Drug discovery from medicinal plants. Life Sci. 2005, 78, 431–441. [Google Scholar]
  2. Sporn, M.B.; Newton, D.L. Chemoprevention of cancer with retinoids. Fed. Proc. 1979, 38, 2528–2534. [Google Scholar]
  3. Aggarwal, B.B.; Vijayalekshmi, R.V.; Sung, B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin. Cancer Res. 2009, 15, 425–430. [Google Scholar]
  4. Lin, W.W.; Karin, M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J. Clin. Invest. 2007, 117, 1175–1183. [Google Scholar]
  5. Aggarwal, B.B.; Shishodia, S.; Sandur, S.K.; Pandey, M.K.; Sethi, G. Inflammation and cancer: how hot is the link? Biochem. Pharmacol. 2006, 72, 1605–1621. [Google Scholar] [CrossRef] [PubMed]
  6. Sporn, M.B.; Suh, N. Chemoprevention of cancer. Carcinogenesis 2000, 21, 525–530. [Google Scholar]
  7. Phillips, D.R.; Rasbery, J.M.; Bartel, B.; Matsuda, S.P. Biosynthetic diversity in plant triterpene cyclization. Curr. Opin. Plant Biol. 2006, 9, 305–314. [Google Scholar]
  8. Kinghorn, A.D.; Balandrin, M.F. Human Medicinal Agents from Plants (ACS Symposium Series); American Chemical Society: Washington, DC, USA, 1993; Volume 534. [Google Scholar]
  9. Medeiros, R.; Otuki, M.F.; Avellar, M.C.; Calixto, J.B. Mechanisms underlying the inhibitory actions of the pentacyclic triterpene alpha-amyrin in the mouse skin inflammation induced by phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Eur. J. Pharmacol. 2007, 559, 227–235. [Google Scholar]
  10. Vitor, C.E.; Figueiredo, C.P.; Hara, D.B.; Bento, A.F.; Mazzuco, T.L.; Calixto, J.B. Therapeutic action and underlying mechanisms of a combination of two pentacyclic triterpenes, alpha- and beta-amyrin, in a mouse model of colitis. Br. J. Pharmacol. 2009, 157, 1034–1044. [Google Scholar]
  11. Haridas, V.; Nishimura, G.; Xu, Z.X.; Connolly, F.; Hanausek, M.; Walaszek, Z.; Zoltaszek, R.; Gutterman, J.U. Avicin D: a protein reactive plant isoprenoid dephosphorylates Stat 3 by regulating both kinase and phosphatase activities. PLoS One 2009, 4, e5578. [Google Scholar]
  12. Xu, Z.X.; Ding, T.; Haridas, V.; Connolly, F.; Gutterman, J.U. Avicin D, a plant triterpenoid, induces cell apoptosis by recruitment of Fas and downstream signaling molecules into lipid rafts. PLoS One 2009, 4, e8532. [Google Scholar]
  13. Zhang, C.; Li, B.; Gaikwad, A.S.; Haridas, V.; Xu, Z.; Gutterman, J.U.; Duvic, M. Avicin D selectively induces apoptosis and downregulates p-STAT-3, bcl-2, and survivin in cutaneous T-cell lymphoma cells. J. Invest. Dermatol. 2008, 128, 2728–2735. [Google Scholar]
  14. Xu, Z.X.; Liang, J.; Haridas, V.; Gaikwad, A.; Connolly, F.P.; Mills, G.B.; Gutterman, J.U. A plant triterpenoid, avicin D, induces autophagy by activation of AMP-activated protein kinase. Cell Death Differ. 2007, 14, 1948–1957. [Google Scholar]
  15. Gaikwad, A.; Poblenz, A.; Haridas, V.; Zhang, C.; Duvic, M.; Gutterman, J. Triterpenoid electrophiles (avicins) suppress heat shock protein-70 and x-linked inhibitor of apoptosis proteins in malignant cells by activation of ubiquitin machinery: implications for proapoptotic activity. Clin. Cancer Res. 2005, 11, 1953–1962. [Google Scholar]
  16. Haridas, V.; Arntzen, C.J.; Gutterman, J.U. Avicins, a family of triterpenoid saponins from Acacia victoriae (Bentham), inhibit activation of nuclear factor-kappaB by inhibiting both its nuclear localization and ability to bind DNA. Proc. Natl. Acad. Sci. USA 2001, 98, 11557–11562. [Google Scholar]
  17. Tang, X.L.; Yang, X.Y.; Jung, H.J.; Kim, S.Y.; Jung, S.Y.; Choi, D.Y.; Park, W.C.; Park, H. Asiatic acid induces colon cancer cell growth inhibition and apoptosis through mitochondrial death cascade. Biol. Pharm. Bull. 2009, 32, 1399–1405. [Google Scholar]
  18. Park, B.C.; Paek, S.H.; Lee, Y.S.; Kim, S.J.; Lee, E.S.; Choi, H.G.; Yong, C.S.; Kim, J.A. Inhibitory effects of asiatic acid on 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol 13-acetate-induced tumor promotion in mice. Biol. Pharm. Bull. 2007, 30, 176–179. [Google Scholar]
  19. Bunpo, P.; Kataoka, K.; Arimochi, H.; Nakayama, H.; Kuwahara, T.; Vinitketkumnuen, U.; Ohnishi, Y. Inhibitory effects of asiatic acid and CPT-11 on growth of HT-29 cells. J. Med. Invest. 2005, 52, 65–73. [Google Scholar]
  20. Gurfinkel, D.M.; Chow, S.; Hurren, R.; Gronda, M.; Henderson, C.; Berube, C.; Hedley, D.W.; Schimmer, A.D. Disruption of the endoplasmic reticulum and increases in cytoplasmic calcium are early events in cell death induced by the natural triterpenoid Asiatic acid. Apoptosis 2006, 11, 1463–1471. [Google Scholar]
  21. Hsu, Y.L.; Kuo, P.L.; Lin, L.T.; Lin, C.C. Asiatic acid, a triterpene, induces apoptosis and cell cycle arrest through activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways in human breast cancer cells. J. Pharmacol. Exp. Ther. 2005, 313, 333–344. [Google Scholar]
  22. Lee, Y.S.; Jin, D.Q.; Kwon, E.J.; Park, S.H.; Lee, E.S.; Jeong, T.C.; Nam, D.H.; Huh, K.; Kim, J.A. Asiatic acid, a triterpene, induces apoptosis through intracellular Ca2+ release and enhanced expression of p53 in HepG2 human hepatoma cells. Cancer Lett. 2002, 186, 83–91. [Google Scholar]
  23. Park, B.C.; Bosire, K.O.; Lee, E.S.; Lee, Y.S.; Kim, J.A. Asiatic acid induces apoptosis in SK-MEL-2 human melanoma cells. Cancer Lett. 2005, 218, 81–90. [Google Scholar]
  24. Yun, K.J.; Kim, J.Y.; Kim, J.B.; Lee, K.W.; Jeong, S.Y.; Park, H.J.; Jung, H.J.; Cho, Y.W.; Yun, K.; Lee, K.T. Inhibition of LPS-induced NO and PGE2 production by asiatic acid via NF-kappa B inactivation in RAW 264.7 macrophages: possible involvement of the IKK and MAPK pathways. Int. Immunopharmacol. 2008, 8, 431–441. [Google Scholar] [CrossRef] [PubMed]
  25. Zhang, W.J.; Hufnagl, P.; Binder, B.R.; Wojta, J. Antiinflammatory activity of astragaloside IV is mediated by inhibition of NF-kappaB activation and adhesion molecule expression. Thromb. Haemost. 2003, 90, 904–914. [Google Scholar]
  26. Chen, Z.; Wu, Q.; Chen, Y.; He, J. Effects of betulinic acid on proliferation and apoptosis in Jurkat cells and its in vitro mechanism. J. Huazhong Univ. Sci. Technol. Med. Sci. 2008, 28, 634–638. [Google Scholar]
  27. Chintharlapalli, S.; Papineni, S.; Ramaiah, S.K.; Safe, S. Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res. 2007, 67, 2816–2823. [Google Scholar]
  28. Ganguly, A.; Das, B.; Roy, A.; Sen, N.; Dasgupta, S.B.; Mukhopadhayay, S.; Majumder, H.K. Betulinic acid, a catalytic inhibitor of topoisomerase I, inhibits reactive oxygen species-mediated apoptotic topoisomerase I-DNA cleavable complex formation in prostate cancer cells but does not affect the process of cell death. Cancer Res. 2007, 67, 11848–11858. [Google Scholar]
  29. Karna, E.; Palka, J.A. Mechanism of betulinic acid inhibition of collagen biosynthesis in human endometrial adenocarcinoma cells. Neoplasma 2009, 56, 361–366. [Google Scholar]
  30. Kasperczyk, H.; La Ferla-Bruhl, K.; Westhoff, M.A.; Behrend, L.; Zwacka, R.M.; Debatin, K.M.; Fulda, S. Betulinic acid as new activator of NF-kappaB: molecular mechanisms and implications for cancer therapy. Oncogene 2005, 24, 6945–6956. [Google Scholar]
  31. Mullauer, F.B.; Kessler, J.H.; Medema, J.P. Betulinic acid induces cytochrome c release and apoptosis in a Bax/Bak-independent, permeability transition pore dependent fashion. Apoptosis 2009, 14, 191–202. [Google Scholar]
  32. Kunnumakkara, A.B.; Nair, A.S.; Sung, B.; Pandey, M.K.; Aggarwal, B.B. Boswellic acid blocks signal transducers and activators of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1. Mol. Cancer Res. 2009, 7, 118–128. [Google Scholar]
  33. Rabi, T.; Shukla, S.; Gupta, S. Betulinic acid suppresses constitutive and TNFalpha-induced NF-kappaB activation and induces apoptosis in human prostate carcinoma PC-3 cells. Mol. Carcinog. 2008, 47, 964–973. [Google Scholar]
  34. Rzeski, W.; Stepulak, A.; Szymanski, M.; Sifringer, M.; Kaczor, J.; Wejksza, K.; Zdzisinska, B.; Kandefer-Szerszen, M. Betulinic acid decreases expression of bcl-2 and cyclin D1, inhibits proliferation, migration and induces apoptosis in cancer cells. Naunyn Schmiedebergs Arch. Pharmacol. 2006, 374, 11–20. [Google Scholar]
  35. Takada, Y.; Aggarwal, B.B. Betulinic acid suppresses carcinogen-induced NF-kappa B activation through inhibition of I kappa B alpha kinase and p65 phosphorylation: abrogation of cyclooxygenase-2 and matrix metalloprotease-9. J. Immunol. 2003, 171, 3278–3286. [Google Scholar]
  36. Thurnher, D.; Turhani, D.; Pelzmann, M.; Wannemacher, B.; Knerer, B.; Formanek, M.; Wacheck, V.; Selzer, E. Betulinic acid: a new cytotoxic compound against malignant head and neck cancer cells. Head Neck 2003, 25, 732–740. [Google Scholar]
  37. Yoon, J.J.; Lee, Y.J.; Kim, J.S.; Kang, D.G.; Lee, H.S. Protective role of betulinic acid on TNF-alpha-induced cell adhesion molecules in vascular endothelial cells. Biochem. Biophys. Res. Commun. 2010, 391, 96–101. [Google Scholar]
  38. Yun, Y.; Han, S.; Park, E.; Yim, D.; Lee, S.; Lee, C.K.; Cho, K.; Kim, K. Immunomodulatory activity of betulinic acid by producing pro-inflammatory cytokines and activation of macrophages. Arch. Pharm. Res. 2003, 26, 1087–1095. [Google Scholar]
  39. Cuaz-Perolin, C.; Billiet, L.; Bauge, E.; Copin, C.; Scott-Algara, D.; Genze, F.; Buchele, B.; Syrovets, T.; Simmet, T.; Rouis, M. Antiinflammatory and antiatherogenic effects of the NF-kappaB inhibitor acetyl-11-keto-beta-boswellic acid in LPS-challenged ApoE-/- mice. Arterioscler. Thromb. Vasc. Biol. 2008, 28, 272–277. [Google Scholar]
  40. Kiela, P.R.; Midura, A.J.; Kuscuoglu, N.; Jolad, S.D.; Solyom, A.M.; Besselsen, D.G.; Timmermann, B.N.; Ghishan, F.K. Effects of Boswellia serrata in mouse models of chemically induced colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 288, G798–G808. [Google Scholar]
  41. Lu, M.; Xia, L.; Hua, H.; Jing, Y. Acetyl-keto-beta-boswellic acid induces apoptosis through a death receptor 5-mediated pathway in prostate cancer cells. Cancer Res. 2008, 68, 1180–1186. [Google Scholar]
  42. Moussaieff, A.; Shohami, E.; Kashman, Y.; Fride, E.; Schmitz, M.L.; Renner, F.; Fiebich, B.L.; Munoz, E.; Ben-Neriah, Y.; Mechoulam, R. Incensole acetate, a novel anti-inflammatory compound isolated from Boswellia resin, inhibits nuclear factor-kappa B activation. Mol. Pharmacol. 2007, 72, 1657–1664. [Google Scholar]
  43. Popovic, M.; Laumonnier, Y.; Burysek, L.; Syrovets, T.; Simmet, T. Thrombin-induced expression of endothelial CX3CL1 potentiates monocyte CCL2 production and transendothelial migration. J. Leukoc. Biol. 2008, 84, 215–223. [Google Scholar]
  44. Syrovets, T.; Buchele, B.; Krauss, C.; Laumonnier, Y.; Simmet, T. Acetyl-boswellic acids inhibit lipopolysaccharide-mediated TNF-alpha induction in monocytes by direct interaction with IkappaB kinases. J. Immunol. 2005, 174, 498–506. [Google Scholar]
  45. Syrovets, T.; Gschwend, J.E.; Buchele, B.; Laumonnier, Y.; Zugmaier, W.; Genze, F.; Simmet, T. Inhibition of IkappaB kinase activity by acetyl-boswellic acids promotes apoptosis in androgen-independent PC-3 prostate cancer cells in vitro and in vivo. J. Biol. Chem. 2005, 280, 6170–6180. [Google Scholar]
  46. Takada, Y.; Ichikawa, H.; Badmaev, V.; Aggarwal, B.B. Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression. J. Immunol. 2006, 176, 3127–3140. [Google Scholar]
  47. Wang, H.; Syrovets, T.; Kess, D.; Buchele, B.; Hainzl, H.; Lunov, O.; Weiss, J.M.; Scharffetter-Kochanek, K.; Simmet, T. Targeting NF-kappa B with a natural triterpenoid alleviates skin inflammation in a mouse model of psoriasis. J. Immunol. 2009, 183, 4755–4763. [Google Scholar]
  48. Yuan, H.Q.; Kong, F.; Wang, X.L.; Young, C.Y.; Hu, X.Y.; Lou, H.X. Inhibitory effect of acetyl-11-keto-beta-boswellic acid on androgen receptor by interference of Sp1 binding activity in prostate cancer cells. Biochem. Pharmacol. 2008, 75, 2112–2121. [Google Scholar]
  49. Jung, H.W.; Chung, Y.S.; Kim, Y.S.; Park, Y.K. Celastrol inhibits production of nitric oxide and proinflammatory cytokines through MAPK signal transduction and NF-kappaB in LPS-stimulated BV-2 microglial cells. Exp. Mol. Med. 2007, 39, 715–721. [Google Scholar]
  50. Kim, D.Y.; Park, J.W.; Jeoung, D.; Ro, J.Y. Celastrol suppresses allergen-induced airway inflammation in a mouse allergic asthma model. Eur. J. Pharmacol. 2009, 612, 98–105. [Google Scholar]
  51. Lee, J.H.; Koo, T.H.; Yoon, H.; Jung, H.S.; Jin, H.Z.; Lee, K.; Hong, Y.S.; Lee, J.J. Inhibition of NF-kappa B activation through targeting I kappa B kinase by celastrol, a quinone methide triterpenoid. Biochem. Pharmacol. 2006, 72, 1311–1321. [Google Scholar]
  52. Sethi, G.; Ahn, K.S.; Pandey, M.K.; Aggarwal, B.B. Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-kappaB-regulated gene products and TAK1-mediated NF-kappaB activation. Blood 2007, 109, 2727–2735. [Google Scholar]
  53. Zhang, T.; Li, Y.; Yu, Y.; Zou, P.; Jiang, Y.; Sun, D. Characterization of celastrol to inhibit hsp90 and cdc37 interaction. J. Biol. Chem. 2009, 284, 35381–35389. [Google Scholar]
  54. Chan, K.T.; Li, K.; Liu, S.L.; Chu, K.H.; Toh, M.; Xie, W.D. Cucurbitacin B inhibits STAT3 and the Raf/MEK/ERK pathway in leukemia cell line K562. Cancer Lett. 2010, 289, 46–52. [Google Scholar]
  55. Lui, V.W.; Yau, D.M.; Wong, E.Y.; Ng, Y.K.; Lau, C.P.; Ho, Y.; Chan, J.P.; Hong, B.; Ho, K.; Cheung, C.S.; Tsang, C.M.; Tsao, S.W.; Chan, A.T. Cucurbitacin I elicits anoikis sensitization, inhibits cellular invasion and in vivo tumor formation ability of nasopharyngeal carcinoma cells. Carcinogenesis 2009, 30, 2085–2094. [Google Scholar]
  56. Sun, C.; Zhang, M.; Shan, X.; Zhou, X.; Yang, J.; Wang, Y.; Li-Ling, J.; Deng, Y. Inhibitory effect of cucurbitacin E on pancreatic cancer cells growth via STAT3 signaling. J. Cancer Res. Clin. Oncol. 2009, 136, 603–610. [Google Scholar]
  57. Sun, J.; Blaskovich, M.A.; Jove, R.; Livingston, S.K.; Coppola, D.; Sebti, S.M. Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity. Oncogene 2005, 24, 3236–3245. [Google Scholar]
  58. Thoennissen, N.H.; Iwanski, G.B.; Doan, N.B.; Okamoto, R.; Lin, P.; Abbassi, S.; Song, J.H.; Yin, D.; Toh, M.; Xie, W.D.; Said, J.W.; Koeffler, H.P. Cucurbitacin B induces apoptosis by inhibition of the JAK/STAT pathway and potentiates antiproliferative effects of gemcitabine on pancreatic cancer cells. Cancer Res. 2009, 69, 5876–5884. [Google Scholar]
  59. Yasuda, S.; Yogosawa, S.; Izutani, Y.; Nakamura, Y.; Watanabe, H.; Sakai, T. Cucurbitacin B induces G(2) arrest and apoptosis via a reactive oxygen species-dependent mechanism in human colon adenocarcinoma SW480 cells. Mol. Nutr. Food Res. 2009, 54, 559–565. [Google Scholar]
  60. Chiang, C.T.; Way, T.D.; Tsai, S.J.; Lin, J.K. Diosgenin, a naturally occurring steroid, suppresses fatty acid synthase expression in HER2-overexpressing breast cancer cells through modulating Akt, mTOR and JNK phosphorylation. FEBS Lett. 2007, 581, 5735–5742. [Google Scholar]
  61. Corbiere, C.; Liagre, B.; Terro, F.; Beneytout, J.L. Induction of antiproliferative effect by diosgenin through activation of p53, release of apoptosis-inducing factor (AIF) and modulation of caspase-3 activity in different human cancer cells. Cell Res. 2004, 14, 188–196. [Google Scholar]
  62. Leger, D.Y.; Liagre, B.; Beneytout, J.L. Role of MAPKs and NF-kappaB in diosgenin-induced megakaryocytic differentiation and subsequent apoptosis in HEL cells. Int. J. Oncol. 2006, 28, 201–207. [Google Scholar]
  63. Raju, J.; Bird, R.P. Diosgenin, a naturally occurring steroid [corrected] saponin suppresses 3-hydroxy-3-methylglutaryl CoA reductase expression and induces apoptosis in HCT-116 human colon carcinoma cells. Cancer Lett. 2007, 255, 194–204. [Google Scholar]
  64. Shishodia, S.; Aggarwal, B.B. Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, I kappa B kinase activation and NF-kappa B-regulated gene expression. Oncogene 2006, 25, 1463–1473. [Google Scholar]
  65. Srinivasan, S.; Koduru, S.; Kumar, R.; Venguswamy, G.; Kyprianou, N.; Damodaran, C. Diosgenin targets Akt-mediated prosurvival signaling in human breast cancer cells. Int. J. Cancer 2009, 125, 961–967. [Google Scholar]
  66. Harikumar, K.B.; Sung, B.; Pandey, M.K.; Guha, S.; Krishnan, S.; Aggarwal, B.B. Escin, a Pentacyclic Triterpene, Chemosensitizes Human Tumor Cells through Inhibition of NF-{kappa}B Signaling Pathway. Mol. Pharmacol. 2010, 77, 818–827. [Google Scholar]
  67. Tan, S.M.; Li, F.; Rajendran, P.; Prem Kumar, A.; Hui, K.M.; Sethi, G. Identification of {beta}-escin as a novel inhibitor of STAT3/JAK2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells. J. Pharmacol. Exp. Ther. 2010. [Google Scholar]
  68. Chen, N.H.; Liu, J.W.; Zhong, J.J. Ganoderic acid Me inhibits tumor invasion through down-regulating matrix metalloproteinases 2/9 gene expression. J. Pharmacol. Sci. 2008, 108, 212–216. [Google Scholar]
  69. Jiang, J.; Grieb, B.; Thyagarajan, A.; Sliva, D. Ganoderic acids suppress growth and invasive behavior of breast cancer cells by modulating AP-1 and NF-kappaB signaling. Int. J. Mol. Med. 2008, 21, 577–584. [Google Scholar]
  70. Li, C.H.; Chen, P.Y.; Chang, U.M.; Kan, L.S.; Fang, W.H.; Tsai, K.S.; Lin, S.B. Ganoderic acid X, a lanostanoid triterpene, inhibits topoisomerases and induces apoptosis of cancer cells. Life Sci. 2005, 77, 252–265. [Google Scholar]
  71. Miyamoto, I.; Liu, J.; Shimizu, K.; Sato, M.; Kukita, A.; Kukita, T.; Kondo, R. Regulation of osteoclastogenesis by ganoderic acid DM isolated from Ganoderma lucidum. Eur. J. Pharmacol. 2009, 602, 1–7. [Google Scholar]
  72. Tang, W.; Liu, J.W.; Zhao, W.M.; Wei, D.Z.; Zhong, J.J. Ganoderic acid T from Ganoderma lucidum mycelia induces mitochondria mediated apoptosis in lung cancer cells. Life Sci. 2006, 80, 205–211. [Google Scholar]
  73. Kim, S.M.; Lee, S.Y.; Cho, J.S.; Son, S.M.; Choi, S.S.; Yun, Y.P.; Yoo, H.S.; Yoon do, Y.; Oh, K.W.; Han, S.B.; Hong, J.T. Combination of ginsenoside Rg3 with docetaxel enhances the susceptibility of prostate cancer cells via inhibition of NF-kappaB. Eur. J. Pharmacol. 2010, 631, 1–9. [Google Scholar]
  74. Liu, T.G.; Huang, Y.; Cui, D.D.; Huang, X.B.; Mao, S.H.; Ji, L.L.; Song, H.B.; Yi, C. Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice. BMC Cancer 2009, 9, 250. [Google Scholar]
  75. Wang, J.; Qiao, L.; Li, Y.; Yang, G. Ginsenoside Rb1 attenuates intestinal ischemia-reperfusion-induced liver injury by inhibiting NF-kappaB activation. Exp. Mol. Med. 2008, 40, 686–698. [Google Scholar]
  76. Zhang, Z.; Li, X.; Lv, W.; Yang, Y.; Gao, H.; Yang, J.; Shen, Y.; Ning, G. Ginsenoside Re reduces insulin resistance through inhibition of c-Jun NH2-terminal kinase and nuclear factor-kappaB. Mol. Endocrinol. 2008, 22, 186–195. [Google Scholar]
  77. Curtin, J.F.; Liu, N.; Candolfi, M.; Xiong, W.; Assi, H.; Yagiz, K.; Edwards, M.R.; Michelsen, K.S.; Kroeger, K.M.; Liu, C.; Muhammad, A.K.; Clark, M.C.; Arditi, M.; Comin-Anduix, B.; Ribas, A.; Lowenstein, P.R.; Castro, M.G. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med. 2009, 6, e10. [Google Scholar]
  78. Hsiang, C.Y.; Lai, I.L.; Chao, D.C.; Ho, T.Y. Differential regulation of activator protein 1 activity by glycyrrhizin. Life Sci. 2002, 70, 1643–1656. [Google Scholar]
  79. Matsui, S.; Sonoda, Y.; Sekiya, T.; Aizu-Yokota, E.; Kasahara, T. Glycyrrhizin derivative inhibits eotaxin 1 production via STAT6 in human lung fibroblasts. Int. Immunopharmacol. 2006, 6, 369–375. [Google Scholar]
  80. Menegazzi, M.; Di Paola, R.; Mazzon, E.; Genovese, T.; Crisafulli, C.; Dal Bosco, M.; Zou, Z.; Suzuki, H.; Cuzzocrea, S. Glycyrrhizin attenuates the development of carrageenan-induced lung injury in mice. Pharmacol. Res. 2008, 58, 22–31. [Google Scholar]
  81. Niwa, K.; Lian, Z.; Onogi, K.; Yun, W.; Tang, L.; Mori, H.; Tamaya, T. Preventive effects of glycyrrhizin on estrogen-related endometrial carcinogenesis in mice. Oncol. Rep. 2007, 17, 617–622. [Google Scholar]
  82. Takei, H.; Baba, Y.; Hisatsune, A.; Katsuki, H.; Miyata, T.; Yokomizo, K.; Isohama, Y. Glycyrrhizin inhibits interleukin-8 production and nuclear factor-kappaB activity in lung epithelial cells, but not through glucocorticoid receptors. J. Pharmacol. Sci. 2008, 106, 460–468. [Google Scholar]
  83. Wang, J.Y.; Guo, J.S.; Li, H.; Liu, S.L.; Zern, M.A. Inhibitory effect of glycyrrhizin on NF-kappaB binding activity in CCl4- plus ethanol-induced liver cirrhosis in rats. Liver 1998, 18, 180–185. [Google Scholar]
  84. Chintharlapalli, S.; Papineni, S.; Jutooru, I.; McAlees, A.; Safe, S. Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisome proliferator-activated receptor {gamma} agonists in colon cancer cells. Mol. Cancer Ther. 2007, 6, 1588–1598. [Google Scholar]
  85. Lee, C.S.; Kim, Y.J.; Lee, M.S.; Han, E.S.; Lee, S.J. 18beta-Glycyrrhetinic acid induces apoptotic cell death in SiHa cells and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity. Life Sci. 2008, 83, 481–489. [Google Scholar]
  86. Satomi, Y.; Nishino, H.; Shibata, S. Glycyrrhetinic acid and related compounds induce G1 arrest and apoptosis in human hepatocellular carcinoma HepG2. Anticancer Res. 2005, 25, 4043–4047. [Google Scholar]
  87. Aktan, F.; Henness, S.; Roufogalis, B.D.; Ammit, A.J. Gypenosides derived from Gynostemma pentaphyllum suppress NO synthesis in murine macrophages by inhibiting iNOS enzymatic activity and attenuating NF-kappaB-mediated iNOS protein expression. Nitric Oxide 2003, 8, 235–242. [Google Scholar]
  88. Chen, J.C.; Lu, K.W.; Lee, J.H.; Yeh, C.C.; Chung, J.G. Gypenosides induced apoptosis in human colon cancer cells through the mitochondria-dependent pathways and activation of caspase-3. Anticancer Res. 2006, 26, 4313–4326. [Google Scholar]
  89. Huang, T.H.; Li, Y.; Razmovski-Naumovski, V.; Tran, V.H.; Li, G.Q.; Duke, C.C.; Roufogalis, B.D. Gypenoside XLIX isolated from Gynostemma pentaphyllum inhibits nuclear factor-kappaB activation via a PPAR-alpha-dependent pathway. J. Biomed. Sci. 2006, 13, 535–548. [Google Scholar]
  90. Huang, T.H.; Tran, V.H.; Roufogalis, B.D.; Li, Y. Gypenoside XLIX, a naturally occurring PPAR-alpha activator, inhibits cytokine-induced vascular cell adhesion molecule-1 expression and activity in human endothelial cells. Eur. J. Pharmacol. 2007, 565, 158–165. [Google Scholar]
  91. Huang, T.H.; Tran, V.H.; Roufogalis, B.D.; Li, Y. Gypenoside XLIX, a naturally occurring gynosaponin, PPAR-alpha dependently inhibits LPS-induced tissue factor expression and activity in human THP-1 monocytic cells. Toxicol. Appl. Pharmacol. 2007, 218, 30–36. [Google Scholar]
  92. Lu, H.F.; Chen, Y.S.; Yang, J.S.; Chen, J.C.; Lu, K.W.; Chiu, T.H.; Liu, K.C.; Yeh, C.C.; Chen, G.W.; Lin, H.J.; Chung, J.G. Gypenosides induced G0/G1 arrest via inhibition of cyclin E and induction of apoptosis via activation of caspases-3 and -9 in human lung cancer A-549 cells. In Vivo 2008, 22, 215–221. [Google Scholar]
  93. Lee, T.K.; Poon, R.T.; Wo, J.Y.; Ma, S.; Guan, X.Y.; Myers, J.N.; Altevogt, P.; Yuen, A.P. Lupeol suppresses cisplatin-induced nuclear factor-kappaB activation in head and neck squamous cell carcinoma and inhibits local invasion and nodal metastasis in an orthotopic nude mouse model. Cancer Res. 2007, 67, 8800–8809. [Google Scholar]
  94. Murtaza, I.; Saleem, M.; Adhami, V.M.; Hafeez, B.B.; Mukhtar, H. Suppression of cFLIP by lupeol, a dietary triterpene, is sufficient to overcome resistance to TRAIL-mediated apoptosis in chemoresistant human pancreatic cancer cells. Cancer Res. 2009, 69, 1156–1165. [Google Scholar]
  95. Nigam, N.; Prasad, S.; George, J.; Shukla, Y. Lupeol induces p53 and cyclin-B-mediated G2/M arrest and targets apoptosis through activation of caspase in mouse skin. Biochem. Biophys. Res. Commun. 2009, 381, 253–258. [Google Scholar]
  96. Prasad, S.; Kalra, N.; Shukla, Y. Induction of apoptosis by lupeol and mango extract in mouse prostate and LNCaP cells. Nutr. Cancer 2008, 60, 120–130. [Google Scholar]
  97. Prasad, S.; Madan, E.; Nigam, N.; Roy, P.; George, J.; Shukla, Y. Induction of apoptosis by lupeol in human epidermoid carcinoma A431 cells through regulation of mitochondrial, Akt/PKB and NFkappaB signaling pathways. Cancer Biol. Ther. 2009, 8, 1632–1639. [Google Scholar]
  98. Saleem, M.; Afaq, F.; Adhami, V.M.; Mukhtar, H. Lupeol modulates NF-kappaB and PI3K/Akt pathways and inhibits skin cancer in CD-1 mice. Oncogene 2004, 23, 5203–5214. [Google Scholar]
  99. Saleem, M.; Kaur, S.; Kweon, M.H.; Adhami, V.M.; Afaq, F.; Mukhtar, H. Lupeol, a fruit and vegetable based triterpene, induces apoptotic death of human pancreatic adenocarcinoma cells via inhibition of Ras signaling pathway. Carcinogenesis 2005, 26, 1956–1964. [Google Scholar]
  100. Saleem, M.; Murtaza, I.; Tarapore, R.S.; Suh, Y.; Adhami, V.M.; Johnson, J.J.; Siddiqui, I.A.; Khan, N.; Asim, M.; Hafeez, B.B.; Shekhani, M.T.; Li, B.; Mukhtar, H. Lupeol inhibits proliferation of human prostate cancer cells by targeting beta-catenin signaling. Carcinogenesis 2009, 30, 808–817. [Google Scholar]
  101. Saleem, M.; Murtaza, I.; Witkowsky, O.; Kohl, A.M.; Maddodi, N. Lupeol triterpene, a novel diet-based microtubule targeting agent: disrupts survivin/cFLIP activation in prostate cancer cells. Biochem. Biophys. Res. Commun. 2009, 388, 576–582. [Google Scholar]
  102. Zhang, L.; Zhang, Y.; Zhang, L.; Yang, X.; Lv, Z. Lupeol, a dietary triterpene, inhibited growth, and induced apoptosis through down-regulation of DR3 in SMMC7721 cells. Cancer Invest 2009, 27, 163–170. [Google Scholar]
  103. Won, J.H.; Shin, J.S.; Park, H.J.; Jung, H.J.; Koh, D.J.; Jo, B.G.; Lee, J.Y.; Yun, K.; Lee, K.T. Anti-inflammatory Effects of Madecassic Acid via the Suppression of NF-kappaB Pathway in LPS-Induced RAW 264.7 Macrophage Cells. Planta Med. 2010, 76, 251–257. [Google Scholar] [CrossRef] [PubMed]
  104. Hwang, Y.H.; Lee, J.W.; Hahm, E.R.; Jung, K.C.; Lee, J.H.; Park, C.H.; Rhee, H.S.; Ryu, J.M.; Kim, H.K.; Yang, C.H. Momordin I, an inhibitor of AP-1, suppressed osteoclastogenesis through inhibition of NF-kappaB and AP-1 and also reduced osteoclast activity and survival. Biochem. Biophys. Res. Commun. 2005, 337, 815–823. [Google Scholar]
  105. Kim, J.H.; Ju, E.M.; Lee, D.K.; Hwang, H.J. Induction of apoptosis by momordin I in promyelocytic leukemia (HL-60) cells. Anticancer Res. 2002, 22, 1885–1889. [Google Scholar]
  106. Afaq, F.; Saleem, M.; Aziz, M.H.; Mukhtar, H. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion markers in CD-1 mouse skin by oleandrin. Toxicol. Appl. Pharmacol. 2004, 195, 361–369. [Google Scholar]
  107. Manna, S.K.; Sah, N.K.; Newman, R.A.; Cisneros, A.; Aggarwal, B.B. Oleandrin suppresses activation of nuclear transcription factor-kappaB, activator protein-1, and c-Jun NH2-terminal kinase. Cancer Res. 2000, 60, 3838–3847. [Google Scholar]
  108. Newman, R.A.; Kondo, Y.; Yokoyama, T.; Dixon, S.; Cartwright, C.; Chan, D.; Johansen, M.; Yang, P. Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid-soluble cardiac glycoside. Integr. Cancer Ther. 2007, 6, 354–364. [Google Scholar]
  109. Smith, J.A.; Madden, T.; Vijjeswarapu, M.; Newman, R.A. Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by Anvirzel and its cardiac glycoside component, oleandrin. Biochem. Pharmacol. 2001, 62, 469–472. [Google Scholar]
  110. Sreenivasan, Y.; Raghavendra, P.B.; Manna, S.K. Oleandrin-mediated expression of Fas potentiates apoptosis in tumor cells. J. Clin. Immunol. 2006, 26, 308–322. [Google Scholar]
  111. Chu, R.; Zhao, X.; Griffin, C.; Staub, R.E.; Shoemaker, M.; Climent, J.; Leitman, D.; Cohen, I.; Shtivelman, E.; Fong, S. Selective concomitant inhibition of mTORC1 and mTORC2 activity in estrogen receptor negative breast cancer cells by BN107 and oleanolic acid. Int. J. Cancer 2009. [Google Scholar]
  112. Deeb, D.; Gao, X.; Dulchavsky, S.A.; Gautam, S.C. CDDO-Me inhibits proliferation, induces apoptosis, down-regulates Akt, mTOR, NF-kappaB and NF-kappaB-regulated antiapoptotic and proangiogenic proteins in TRAMP prostate cancer cells. J. Exp. Ther. Oncol. 2008, 7, 31–39. [Google Scholar]
  113. Deeb, D.; Gao, X.; Jiang, H.; Janic, B.; Arbab, A.S.; Rojanasakul, Y.; Dulchavsky, S.A.; Gautam, S.C. Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism. Biochem. Pharmacol. 2010, 79, 350–360. [Google Scholar]
  114. Yan, S.L.; Huang, C.Y.; Wu, S.T.; Yin, M.C. Oleanolic acid and ursolic acid induce apoptosis in four human liver cancer cell lines. Toxicol in Vitro 24, 842–848. [PubMed]
  115. Ahn, K.S.; Hahn, B.S.; Kwack, K.; Lee, E.B.; Kim, Y.S. Platycodin D-induced apoptosis through nuclear factor-kappaB activation in immortalized keratinocytes. Eur. J. Pharmacol. 2006, 537, 1–11. [Google Scholar]
  116. Shin, D.Y.; Kim, G.Y.; Li, W.; Choi, B.T.; Kim, N.D.; Kang, H.S.; Choi, Y.H. Implication of intracellular ROS formation, caspase-3 activation and Egr-1 induction in platycodon D-induced apoptosis of U937 human leukemia cells. Biomed. Pharmacother. 2009, 63, 86–94. [Google Scholar]
  117. Byun, J.Y.; Kim, M.J.; Eum, D.Y.; Yoon, C.H.; Seo, W.D.; Park, K.H.; Hyun, J.W.; Lee, Y.S.; Lee, J.S.; Yoon, M.Y.; Lee, S.J. Reactive oxygen species-dependent activation of Bax and poly(ADP-ribose) polymerase-1 is required for mitochondrial cell death induced by triterpenoid pristimerin in human cervical cancer cells. Mol. Pharmacol. 2009, 76, 734–744. [Google Scholar]
  118. Tiedemann, R.E.; Schmidt, J.; Keats, J.J.; Shi, C.X.; Zhu, Y.X.; Palmer, S.E.; Mao, X.; Schimmer, A.D.; Stewart, A.K. Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-kappaB with antimyeloma activity in vitro and in vivo. Blood 2009, 113, 4027–4037. [Google Scholar]
  119. Wu, C.C.; Chan, M.L.; Chen, W.Y.; Tsai, C.Y.; Chang, F.R.; Wu, Y.C. Pristimerin induces caspase-dependent apoptosis in MDA-MB-231 cells via direct effects on mitochondria. Mol. Cancer Ther. 2005, 4, 1277–1285. [Google Scholar]
  120. Yang, H.; Landis-Piwowar, K.R.; Lu, D.; Yuan, P.; Li, L.; Reddy, G.P.; Yuan, X.; Dou, Q.P. Pristimerin induces apoptosis by targeting the proteasome in prostate cancer cells. J. Cell Biochem. 2008, 103, 234–244. [Google Scholar]
  121. Hsu, Y.L.; Kuo, P.L.; Chiang, L.C.; Lin, C.C. Involvement of p53, nuclear factor kappaB and Fas/Fas ligand in induction of apoptosis and cell cycle arrest by saikosaponin d in human hepatoma cell lines. Cancer Lett. 2004, 213, 213–221. [Google Scholar]
  122. Leung, C.Y.; Liu, L.; Wong, R.N.; Zeng, Y.Y.; Li, M.; Zhou, H. Saikosaponin-d inhibits T cell activation through the modulation of PKCtheta, JNK, and NF-kappaB transcription factor. Biochem. Biophys. Res. Commun. 2005, 338, 1920–1927. [Google Scholar]
  123. Wong, V.K.; Zhou, H.; Cheung, S.S.; Li, T.; Liu, L. Mechanistic study of saikosaponin-d (Ssd) on suppression of murine T lymphocyte activation. J. Cell Biochem. 2009, 107, 303–315. [Google Scholar]
  124. Manu, K.A.; Kuttan, G. Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-kappaB mediated activation of bcl-2 in B16F-10 melanoma cells. Int. Immunopharmacol. 2008, 8, 974–981. [Google Scholar]
  125. Shishodia, S.; Majumdar, S.; Banerjee, S.; Aggarwal, B.B. Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res. 2003, 63, 4375–4383. [Google Scholar]
  126. Achiwa, Y.; Hasegawa, K.; Udagawa, Y. Regulation of the phosphatidylinositol 3-kinase-Akt and the mitogen-activated protein kinase pathways by ursolic acid in human endometrial cancer cells. Biosci. Biotechnol. Biochem. 2007, 71, 31–37. [Google Scholar]
  127. Huang, H.C.; Huang, C.Y.; Lin-Shiau, S.Y.; Lin, J.K. Ursolic acid inhibits IL-1beta or TNF-alpha-induced C6 glioma invasion through suppressing the association ZIP/p62 with PKC-zeta and downregulating the MMP-9 expression. Mol. Carcinog. 2009, 48, 517–531. [Google Scholar]
  128. Li, Y.; Xing, D.; Chen, Q.; Chen, W.R. Enhancement of chemotherapeutic agent-induced apoptosis by inhibition of NF-kappaB using ursolic acid. Int. J. Cancer 2010, 127, 462–473. [Google Scholar]
  129. Pathak, A.K.; Bhutani, M.; Nair, A.S.; Ahn, K.S.; Chakraborty, A.; Kadara, H.; Guha, S.; Sethi, G.; Aggarwal, B.B. Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol. Cancer Res. 2007, 5, 943–955. [Google Scholar]
  130. Shan, J.Z.; Xuan, Y.Y.; Zheng, S.; Dong, Q.; Zhang, S.Z. Ursolic acid inhibits proliferation and induces apoptosis of HT-29 colon cancer cells by inhibiting the EGFR/MAPK pathway. J. Zhejiang Univ. Sci. B 2009, 10, 668–674. [Google Scholar]
  131. Wang, X.; Li, L.; Wang, B.; Xiang, J. Effects of ursolic acid on the proliferation and apoptosis of human ovarian cancer cells. J. Huazhong Univ. Sci. Technol. Med. Sci. 2009, 29, 761–764. [Google Scholar]
  132. Zhang, Y.X.; Kong, C.Z.; Wang, L.H.; Li, J.Y.; Liu, X.K.; Xu, B.; Xu, C.L.; Sun, Y.H. Ursolic acid overcomes Bcl-2-mediated resistance to apoptosis in prostate cancer cells involving activation of JNK-induced Bcl-2 phosphorylation and degradation. J. Cell Biochem. 2010, 109, 764–773. [Google Scholar]
  133. Chang, H.C.; Chang, F.R.; Wang, Y.C.; Pan, M.R.; Hung, W.C.; Wu, Y.C. A bioactive withanolide Tubocapsanolide A inhibits proliferation of human lung cancer cells via repressing Skp2 expression. Mol. Cancer Ther. 2007, 6, 1572–1578. [Google Scholar]
  134. Chen, W.Y.; Chang, F.R.; Huang, Z.Y.; Chen, J.H.; Wu, Y.C.; Wu, C.C. Tubocapsenolide A, a novel withanolide, inhibits proliferation and induces apoptosis in MDA-MB-231 cells by thiol oxidation of heat shock proteins. J. Biol. Chem. 2008, 283, 17184–17193. [Google Scholar]
  135. Ichikawa, H.; Takada, Y.; Shishodia, S.; Jayaprakasam, B.; Nair, M.G.; Aggarwal, B.B. Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-kappaB (NF-kappaB) activation and NF-kappaB-regulated gene expression. Mol. Cancer Ther. 2006, 5, 1434–1445. [Google Scholar]
  136. Malik, F.; Kumar, A.; Bhushan, S.; Khan, S.; Bhatia, A.; Suri, K.A.; Qazi, G.N.; Singh, J. Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic cell death of human myeloid leukemia HL-60 cells by a dietary compound withaferin A with concomitant protection by N-acetyl cysteine. Apoptosis 2007, 12, 2115–2133. [Google Scholar]
  137. Mulabagal, V.; Subbaraju, G.V.; Rao, C.V.; Sivaramakrishna, C.; Dewitt, D.L.; Holmes, D.; Sung, B.; Aggarwal, B.B.; Tsay, H.S.; Nair, M.G. Withanolide sulfoxide from Aswagandha roots inhibits nuclear transcription factor-kappa-B, cyclooxygenase and tumor cell proliferation. Phytother. Res. 2009, 23, 987–992. [Google Scholar]
  138. Ndlovu, N.; van Lint, C.; Van Wesemael, K.; Callebert, P.; Chalbos, D.; Haegeman, G.; Vanden Berghe, W. Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells. Mol. Cell Biol. 2009, 29, 5488–5504. [Google Scholar]
  139. Liu, J. Pharmacology of oleanolic acid and ursolic acid. J. Ethnopharmacol. 1995, 49, 57–68. [Google Scholar]
  140. Bouvier, F.; Rahier, A.; Camara, B. Biogenesis, molecular regulation and function of plant isoprenoids. Prog. Lipid Res. 2005, 44, 357–429. [Google Scholar]
  141. Keeling, C.I.; Bohlmann, J. Genes, enzymes and chemicals of terpenoid diversity in the constitutive and induced defence of conifers against insects and pathogens. New Phytol. 2006, 170, 657–675. [Google Scholar]
  142. Franceschi, V.R.; Krokene, P.; Christiansen, E.; Krekling, T. Anatomical and chemical defenses of conifer bark against bark beetles and other pests. New Phytol. 2005, 167, 353–375. [Google Scholar]
  143. Kumar, A.; Takada, Y.; Boriek, A.M.; Aggarwal, B.B. Nuclear factor-kappaB: its role in health and disease. J. Mol. Med. 2004, 82, 434–448. [Google Scholar]
  144. Garcia, R.; Yu, C.L.; Hudnall, A.; Catlett, R.; Nelson, K.L.; Smithgall, T.; Fujita, D.J.; Ethier, S.P.; Jove, R. Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Differ. 1997, 8, 1267–1276. [Google Scholar]
  145. Kim, Y.K.; Kim, R.G.; Park, S.J.; Ha, J.H.; Choi, J.W.; Park, H.J.; Lee, K.T. In vitro antiinflammatory activity of kalopanaxsaponin A isolated from Kalopanax pictus in murine macrophage RAW 264.7 cells. Biol. Pharm. Bull. 2002, 25, 472–476. [Google Scholar] [CrossRef] [PubMed]
  146. Tian, Z.; Yang, M.; Huang, F.; Li, K.; Si, J.; Shi, L.; Chen, S.; Xiao, P. Cytotoxicity of three cycloartane triterpenoids from Cimicifuga dahurica. Cancer Lett. 2005, 226, 65–75. [Google Scholar]
  147. Migone, T.S.; Lin, J.X.; Cereseto, A.; Mulloy, J.C.; O'Shea, J.J.; Franchini, G.; Leonard, W.J. Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. Science 1995, 269, 79–81. [Google Scholar]
  148. Megeney, L.A.; Perry, R.L.; LeCouter, J.E.; Rudnicki, M.A. bFGF and LIF signaling activates STAT3 in proliferating myoblasts. Dev. Genet. 1996, 19, 139–145. [Google Scholar]
  149. Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature 2002, 420, 860–867. [Google Scholar]
  150. Karin, M.; Cao, Y.; Greten, F.R.; Li, Z.W. NF-kappaB in cancer: from innocent bystander to major culprit. Nat. Rev. Cancer 2002, 2, 301–310. [Google Scholar]
  151. Hayden, M.S.; Ghosh, S. Signaling to NF-kappaB. Genes Dev. 2004, 18, 2195–2224. [Google Scholar]
  152. Janssens, S.; Tschopp, J. Signals from within: the DNA-damage-induced NF-kappaB response. Cell Death Differ. 2006, 13, 773–784. [Google Scholar]
  153. Karin, M.; Greten, F.R. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 2005, 5, 749–759. [Google Scholar]
  154. Bonizzi, G.; Karin, M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 2004, 25, 280–288. [Google Scholar]
  155. Xie, K. Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev. 2001, 12, 375–391. [Google Scholar]
  156. Garg, A.; Aggarwal, B.B. Nuclear transcription factor-kappaB as a target for cancer drug development. Leukemia 2002, 16, 1053–1068. [Google Scholar]
  157. Nathan, C. Points of control in inflammation. Nature 2002, 420, 846–852. [Google Scholar]
  158. Balkwill, F.; Charles, K.A.; Mantovani, A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 2005, 7, 211–217. [Google Scholar]
  159. Ulrich, C.M.; Potter, J.D. Testing for colon neoplasia susceptibility variants at the human Cox2 locus. J. Natl. Cancer Inst. 2001, 93, 1572–1574. [Google Scholar]
  160. Suh, N.; Wang, Y.; Honda, T.; Gribble, G.W.; Dmitrovsky, E.; Hickey, W.F.; Maue, R.A.; Place, A.E.; Porter, D.M.; Spinella, M.J.; Williams, C.R.; Wu, G.; Dannenberg, A.J.; Flanders, K.C.; Letterio, J.J.; Mangelsdorf, D.J.; Nathan, C.F.; Nguyen, L.; Porter, W.W.; Ren, R.F.; Roberts, A.B.; Roche, N.S.; Subbaramaiah, K.; Sporn, M.B. A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity. Cancer Res. 1999, 59, 336–341. [Google Scholar]
  161. Suh, N.; Roberts, A.B.; Birkey Reffey, S.; Miyazono, K.; Itoh, S.; ten Dijke, P.; Heiss, E.H.; Place, A.E.; Risingsong, R.; Williams, C.R.; Honda, T.; Gribble, G.W.; Sporn, M.B. Synthetic triterpenoids enhance transforming growth factor beta/Smad signaling. Cancer Res. 2003, 63, 1371–1376. [Google Scholar]
  162. Suh, W.S.; Kim, Y.S.; Schimmer, A.D.; Kitada, S.; Minden, M.; Andreeff, M.; Suh, N.; Sporn, M.; Reed, J.C. Synthetic triterpenoids activate a pathway for apoptosis in AML cells involving downregulation of FLIP and sensitization to TRAIL. Leukemia 2003, 17, 2122–2129. [Google Scholar]
  163. Ahmad, R.; Raina, D.; Meyer, C.; Kharbanda, S.; Kufe, D. Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179. J. Biol. Chem. 2006, 281, 35764–35769. [Google Scholar]
  164. Yore, M.M.; Liby, K.T.; Honda, T.; Gribble, G.W.; Sporn, M.B. The synthetic triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole blocks nuclear factor-kappaB activation through direct inhibition of IkappaB kinase beta. Mol. Cancer Ther. 2006, 5, 3232–3239. [Google Scholar]
  165. Couch, R.D.; Browning, R.G.; Honda, T.; Gribble, G.W.; Wright, D.L.; Sporn, M.B.; Anderson, A.C. Studies on the reactivity of CDDO, a promising new chemopreventive and chemotherapeutic agent: implications for a molecular mechanism of action. Bioorg. Med. Chem. Lett 2005, 15, 2215–2219. [Google Scholar]
  166. Haridas, V.; Kim, S.O.; Nishimura, G.; Hausladen, A.; Stamler, J.S.; Gutterman, J.U. Avicinylation (thioesterification): a protein modification that can regulate the response to oxidative and nitrosative stress. Proc. Natl. Acad. Sci. USA 2005, 102, 10088–10093. [Google Scholar]
  167. Deeb, D.; Gao, X.; Jiang, H.; Dulchavsky, S.A.; Gautam, S.C. Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells by independently targeting pro-survival Akt and mTOR. Prostate 2009, 69, 851–860. [Google Scholar]
  168. Dirsch, V.M.; Kiemer, A.K.; Wagner, H.; Vollmar, A.M. The triterpenoid quinonemethide pristimerin inhibits induction of inducible nitric oxide synthase in murine macrophages. Eur. J. Pharmacol. 1997, 336, 211–217. [Google Scholar]
  169. Brunelleschi, S.; Bardelli, C.; Amoruso, A.; Gunella, G.; Ieri, F.; Romani, A.; Malorni, W.; Franconi, F. Minor polar compounds extra-virgin olive oil extract (MPC-OOE) inhibits NF-kappa B translocation in human monocyte/macrophages. Pharmacol. Res. 2007, 56, 542–549. [Google Scholar]
  170. Tundis, R.; Bonesi, M.; Deguin, B.; Loizzo, M.R.; Menichini, F.; Conforti, F.; Tillequin, F.; Menichini, F. Cytotoxic activity and inhibitory effect on nitric oxide production of triterpene saponins from the roots of Physospermum verticillatum (Waldst & Kit) (Apiaceae). Bioorg. Med. Chem. 2009, 17, 4542–4547. [Google Scholar]
  171. Yesilada, E.; Bedir, E.; Calis, I.; Takaishi, Y.; Ohmoto, Y. Effects of triterpene saponins from Astragalus species on in vitro cytokine release. J. Ethnopharmacol. 2005, 96, 71–77. [Google Scholar]
  172. Chang, U.M.; Li, C.H.; Lin, L.I.; Huang, C.P.; Kan, L.S.; Lin, S.B. Ganoderiol F, a ganoderma triterpene, induces senescence in hepatoma HepG2 cells. Life Sci. 2006, 79, 1129–1139. [Google Scholar]
  173. Lu, K.W.; Tsai, M.L.; Chen, J.C.; Hsu, S.C.; Hsia, T.C.; Lin, M.W.; Huang, A.C.; Chang, Y.H.; Ip, S.W.; Lu, H.F.; Chung, J.G. Gypenosides inhibited invasion and migration of human tongue cancer SCC4 cells through down-regulation of NFkappaB and matrix metalloproteinase-9. Anticancer Res. 2008, 28, 1093–1099. [Google Scholar]
  174. Park, Y.S.; Lee, J.H.; Bondar, J.; Harwalkar, J.A.; Safayhi, H.; Golubic, M. Cytotoxic action of acetyl-11-keto-beta-boswellic acid (AKBA) on meningioma cells. Planta Med. 2002, 68, 397–401. [Google Scholar]
  175. Lee, K.J.; Hwang, S.J.; Choi, J.H.; Jeong, H.G. Saponins derived from the roots of Platycodon grandiflorum inhibit HT-1080 cell invasion and MMPs activities: regulation of NF-kappaB activation via ROS signal pathway. Cancer Lett. 2008, 268, 233–243. [Google Scholar]
  176. Kim, M.O.; Moon, D.O.; Choi, Y.H.; Shin, D.Y.; Kang, H.S.; Choi, B.T.; Lee, J.D.; Li, W.; Kim, G.Y. Platycodin D induces apoptosis and decreases telomerase activity in human leukemia cells. Cancer Lett. 2008, 261, 98–107. [Google Scholar]
  177. Xie, Y.; Ye, Y.P.; Sun, H.X.; Li, D. Contribution of the glycidic moieties to the haemolytic and adjuvant activity of platycodigenin-type saponins from the root of Platycodon grandiflorum. Vaccine 2008, 26, 3452–3460. [Google Scholar]
  178. Fulda, S.; Debatin, K.M. Signaling through death receptors in cancer therapy. Curr. Opin. Pharmacol. 2004, 4, 327–332. [Google Scholar]
  179. Fesik, S.W.; Shi, Y. Structural biology. Controlling the caspases. Science 2001, 294, 1477–1478. [Google Scholar] [CrossRef] [PubMed]
  180. Ashkenazi, A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat. Rev. Cancer 2002, 2, 420–430. [Google Scholar]
  181. Debatin, K.M.; Krammer, P.H. Death receptors in chemotherapy and cancer. Oncogene 2004, 23, 2950–2966. [Google Scholar]
  182. Rieger, L.; Weller, M.; Bornemann, A.; Schabet, M.; Dichgans, J.; Meyermann, R. BCL-2 family protein expression in human malignant glioma: a clinical-pathological correlative study. J. Neurol. Sci. 1998, 155, 68–75. [Google Scholar]
  183. Gerhauser, C. Cancer chemopreventive potential of apples, apple juice, and apple components. Planta Med. 2008, 74, 1608–1624. [Google Scholar]
  184. Costa, P.M.; Ferreira, P.M.; Bolzani Vda, S.; Furlan, M.; de Freitas Formenton Macedo Dos Santos, V.A.; Corsino, J.; de Moraes, M.O.; Costa-Lotufo, L.V.; Montenegro, R.C.; Pessoa, C. Antiproliferative activity of pristimerin isolated from Maytenus ilicifolia (Celastraceae) in human HL-60 cells. Toxicol in Vitro 2008, 22, 854–863. [Google Scholar]
  185. Murayama, T.; Eizuru, Y.; Yamada, R.; Sadanari, H.; Matsubara, K.; Rukung, G.; Tolo, F.M.; Mungai, G.M.; Kofi-Tsekpo, M. Anticytomegalovirus activity of pristimerin, a triterpenoid quinone methide isolated from Maytenus heterophylla (Eckl. & Zeyh.). Antivir. Chem. Chemother. 2007, 18, 133–139. [Google Scholar] [PubMed]
  186. Liagre, B.; Bertrand, J.; Leger, D.Y.; Beneytout, J.L. Diosgenin, a plant steroid, induces apoptosis in COX-2 deficient K562 cells with activation of the p38 MAP kinase signalling and inhibition of NF-kappaB binding. Int. J. Mol. Med. 2005, 16, 1095–1101. [Google Scholar]
  187. Haridas, V.; Li, X.; Mizumachi, T.; Higuchi, M.; Lemeshko, V.V.; Colombini, M.; Gutterman, J.U. Avicins, a novel plant-derived metabolite lowers energy metabolism in tumor cells by targeting the outer mitochondrial membrane. Mitochondrion 2007, 7, 234–240. [Google Scholar]
  188. Pandey, M.K.; Sung, B.; Aggarwal, B.B. Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP-1 in human multiple myeloma cells. Int. J. Cancer 2010, 127, 282–292. [Google Scholar]
  189. Martin, R.; Ibeas, E.; Carvalho-Tavares, J.; Hernandez, M.; Ruiz-Gutierrez, V.; Nieto, M.L. Natural triterpenic diols promote apoptosis in astrocytoma cells through ROS-mediated mitochondrial depolarization and JNK activation. PLoS One 2009, 4, e5975. [Google Scholar]
  190. Martinez-Gonzalez, J.; Rodriguez-Rodriguez, R.; Gonzalez-Diez, M.; Rodriguez, C.; Herrera, M.D.; Ruiz-Gutierrez, V.; Badimon, L. Oleanolic acid induces prostacyclin release in human vascular smooth muscle cells through a cyclooxygenase-2-dependent mechanism. J. Nutr. 2008, 138, 443–448. [Google Scholar]
  191. Reyes, F.J.; Centelles, J.J.; Lupianez, J.A.; Cascante, M. (2Alpha,3beta)-2,3-dihydroxyolean-12-en-28-oic acid, a new natural triterpene from Olea europea, induces caspase dependent apoptosis selectively in colon adenocarcinoma cells. FEBS Lett. 2006, 580, 6302–6310. [Google Scholar] [CrossRef] [PubMed]
  192. Chen, J.C.; Chang, N.W.; Chung, J.G.; Chen, K.C. Saikosaponin-A induces apoptotic mechanism in human breast MDA-MB-231 and MCF-7 cancer cells. Am. J. Chin. Med. 2003, 31, 363–377. [Google Scholar]
  193. Hsu, M.J.; Cheng, J.S.; Huang, H.C. Effect of saikosaponin, a triterpene saponin, on apoptosis in lymphocytes: association with c-myc, p53, and bcl-2 mRNA. Br. J. Pharmacol. 2000, 131, 1285–1293. [Google Scholar]
  194. Sun, Y.; Cai, T.T.; Zhou, X.B.; Xu, Q. Saikosaponin a inhibits the proliferation and activation of T cells through cell cycle arrest and induction of apoptosis. Int. Immunopharmacol. 2009, 9, 978–983. [Google Scholar]
  195. Siu, F.M.; Ma, D.L.; Cheung, Y.W.; Lok, C.N.; Yan, K.; Yang, Z.; Yang, M.; Xu, S.; Ko, B.C.; He, Q.Y.; Che, C.M. Proteomic and transcriptomic study on the action of a cytotoxic saponin (Polyphyllin D): induction of endoplasmic reticulum stress and mitochondria-mediated apoptotic pathways. Proteomics 2008, 8, 3105–3117. [Google Scholar]
  196. Zou, W.; Liu, X.; Yue, P.; Zhou, Z.; Sporn, M.B.; Lotan, R.; Khuri, F.R.; Sun, S.Y. c-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in human lung cancer cells. Cancer Res. 2004, 64, 7570–7578. [Google Scholar]
  197. Pedersen, I.M.; Kitada, S.; Schimmer, A.; Kim, Y.; Zapata, J.M.; Charboneau, L.; Rassenti, L.; Andreeff, M.; Bennett, F.; Sporn, M.B.; Liotta, L.D.; Kipps, T.J.; Reed, J.C. The triterpenoid CDDO induces apoptosis in refractory CLL B cells. Blood 2002, 100, 2965–2972. [Google Scholar]
  198. Liu, J.J.; Duan, R.D. LY294002 enhances boswellic acid-induced apoptosis in colon cancer cells. Anticancer Res. 2009, 29, 2987–2991. [Google Scholar]
  199. Liu, J.J.; Huang, B.; Hooi, S.C. Acetyl-keto-beta-boswellic acid inhibits cellular proliferation through a p21-dependent pathway in colon cancer cells. Br. J. Pharmacol. 2006, 148, 1099–1107. [Google Scholar]
  200. Hostanska, K.; Daum, G.; Saller, R. Cytostatic and apoptosis-inducing activity of boswellic acids toward malignant cell lines in vitro. Anticancer Res. 2002, 22, 2853–2862. [Google Scholar]
  201. Liu, J.J.; Nilsson, A.; Oredsson, S.; Badmaev, V.; Zhao, W.Z.; Duan, R.D. Boswellic acids trigger apoptosis via a pathway dependent on caspase-8 activation but independent on Fas/Fas ligand interaction in colon cancer HT-29 cells. Carcinogenesis 2002, 23, 2087–2093. [Google Scholar]
  202. Kim, J.Y.; Park, K.W.; Moon, K.D.; Lee, M.K.; Choi, J.; Yee, S.T.; Shim, K.H.; Seo, K.I. Induction of apoptosis in HT-29 colon cancer cells by crude saponin from Platycodi Radix. Food Chem. Toxicol. 2008, 46, 3753–3758. [Google Scholar]
  203. Park, D.I.; Lee, J.H.; Moon, S.K.; Kim, C.H.; Lee, Y.T.; Cheong, J.; Choi, B.T.; Choi, Y.H. Induction of apoptosis and inhibition of telomerase activity by aqueous extract from Platycodon grandiflorum in human lung carcinoma cells. Pharmacol. Res. 2005, 51, 437–443. [Google Scholar]
  204. Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell 2000, 100, 57–70. [Google Scholar]
  205. He, X.; Liu, R.H. Triterpenoids isolated from apple peels have potent antiproliferative activity and may be partially responsible for apple's anticancer activity. J. Agric. Food Chem. 2007, 55, 4366–4370. [Google Scholar]
  206. Juan, M.E.; Planas, J.M.; Ruiz-Gutierrez, V.; Daniel, H.; Wenzel, U. Antiproliferative and apoptosis-inducing effects of maslinic and oleanolic acids, two pentacyclic triterpenes from olives, on HT-29 colon cancer cells. Br. J. Nutr. 2008, 100, 36–43. [Google Scholar]
  207. Juan, M.E.; Wenzel, U.; Ruiz-Gutierrez, V.; Daniel, H.; Planas, J.M. Olive fruit extracts inhibit proliferation and induce apoptosis in HT-29 human colon cancer cells. J. Nutr. 2006, 136, 2553–2557. [Google Scholar]
  208. Marquez Martin, A.; de la Puerta Vazquez, R.; Fernandez-Arche, A.; Ruiz-Gutierrez, V. Supressive effect of maslinic acid from pomace olive oil on oxidative stress and cytokine production in stimulated murine macrophages. Free Radic. Res. 2006, 40, 295–302. [Google Scholar] [CrossRef] [PubMed]
  209. Wang, P.; Ren, J.; Tang, J.; Zhang, D.; Li, B.; Li, Y. Estrogen-like activities of saikosaponin-d in vitro: a pilot study. Eur. J. Pharmacol. 626, 159–165. [PubMed]
  210. Zu, N.; Li, P.; Li, N.; Choy, P.; Gong, Y. Mechanism of saikosaponin-d in the regulation of rat mesangial cell proliferation and synthesis of extracellular matrix proteins. Biochem. Cell Biol. 2007, 85, 169–174. [Google Scholar]
  211. Jedinak, A.; Muckova, M.; Kost'alova, D.; Maliar, T.; Masterova, I. Antiprotease and antimetastatic activity of ursolic acid isolated from Salvia officinalis. Z Naturforsch C 2006, 61, 777–782. [Google Scholar]
  212. Suh, N.; Honda, T.; Finlay, H.J.; Barchowsky, A.; Williams, C.; Benoit, N.E.; Xie, Q.W.; Nathan, C.; Gribble, G.W.; Sporn, M.B. Novel triterpenoids suppress inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in mouse macrophages. Cancer Res. 1998, 58, 717–723. [Google Scholar]
  213. Sawada, N.; Kataoka, K.; Kondo, K.; Arimochi, H.; Fujino, H.; Takahashi, Y.; Miyoshi, T.; Kuwahara, T.; Monden, Y.; Ohnishi, Y. Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice. Br. J. Cancer 2004, 90, 1672–1678. [Google Scholar]
  214. Noujaim, D.; van Golen, C.M.; van Golen, K.L.; Grauman, A.; Feldman, E.L. N-Myc and Bcl-2 coexpression induces MMP-2 secretion and activation in human neuroblastoma cells. Oncogene 2002, 21, 4549–4557. [Google Scholar]
  215. Pan, M.R.; Chang, H.C.; Wu, Y.C.; Huang, C.C.; Hung, W.C. Tubocapsanolide A inhibits transforming growth factor-beta-activating kinase 1 to suppress NF-kappaB-induced CCR7. J. Biol. Chem. 2009, 284, 2746–2754. [Google Scholar]
  216. Moon, H.I.; Kim, M.R.; Woo, E.R.; Chung, J.H. Triterpenoid from Styrax japonica SIEB. et ZUCC, and its effects on the expression of matrix metalloproteinases-1 and type 1 procollagen caused by ultraviolet irradiated cultured primary human skin fibroblasts. Biol. Pharm. Bull. 2005, 28, 2003–2006. [Google Scholar] [CrossRef] [PubMed]
  217. Weng, C.J.; Chau, C.F.; Chen, K.D.; Chen, D.H.; Yen, G.C. The anti-invasive effect of lucidenic acids isolated from a new Ganoderma lucidum strain. Mol. Nutr. Food Res. 2007, 51, 1472–1477. [Google Scholar]
  218. McMahon, G. VEGF receptor signaling in tumor angiogenesis. Oncologist 2000, 5 (Suppl. 1), 3–10. [Google Scholar] [CrossRef] [PubMed]
  219. Shyu, K.G.; Tsai, S.C.; Wang, B.W.; Liu, Y.C.; Lee, C.C. Saikosaponin C induces endothelial cells growth, migration and capillary tube formation. Life Sci. 2004, 76, 813–826. [Google Scholar]
  220. Wang, B.F.; Cheng, Y.A.; Dang, S.S. Angiogenesis inhibitory effect of saikosaponin-d on chicken embryo. Zhongguo Zhong Xi Yi Jie He Za Zhi 2009, 29, 425–429. [Google Scholar]
  221. Sogno, I.; Vannini, N.; Lorusso, G.; Cammarota, R.; Noonan, D.M.; Generoso, L.; Sporn, M.B.; Albini, A. Anti-angiogenic activity of a novel class of chemopreventive compounds: oleanic acid terpenoids. Recent Results Cancer Res. 2009, 181, 209–212. [Google Scholar]
  222. Shishodia, S.; Sethi, G.; Konopleva, M.; Andreeff, M.; Aggarwal, B.B. A synthetic triterpenoid, CDDO-Me, inhibits IkappaBalpha kinase and enhances apoptosis induced by TNF and chemotherapeutic agents through down-regulation of expression of nuclear factor kappaB-regulated gene products in human leukemic cells. Clin. Cancer Res. 2006, 12, 1828–1838. [Google Scholar]
  223. Pang, X.; Yi, Z.; Zhang, X.; Sung, B.; Qu, W.; Lian, X.; Aggarwal, B.B.; Liu, M. Acetyl-11-keto-beta-boswellic acid inhibits prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. Cancer Res. 2009, 69, 5893–5900. [Google Scholar]
  224. Kwon, H.J.; Shim, J.S.; Kim, J.H.; Cho, H.Y.; Yum, Y.N.; Kim, S.H.; Yu, J. Betulinic acid inhibits growth factor-induced in vitro angiogenesis via the modulation of mitochondrial function in endothelial cells. Jpn. J. Cancer Res. 2002, 93, 417–425. [Google Scholar]
  225. Zhou, Y.X.; Huang, Y.L. Antiangiogenic effect of celastrol on the growth of human glioma: an in vitro and in vivo study. Chin. Med. J. (Engl.) 2009, 122, 1666–1673. [Google Scholar] [PubMed]
  226. Kimura, Y.; Taniguchi, M.; Baba, K. Antitumor and antimetastatic effects on liver of triterpenoid fractions of Ganoderma lucidum: mechanism of action and isolation of an active substance. Anticancer Res. 2002, 22, 3309–3318. [Google Scholar]

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Yadav, V.R.; Prasad, S.; Sung, B.; Kannappan, R.; Aggarwal, B.B. Targeting Inflammatory Pathways by Triterpenoids for Prevention and Treatment of Cancer. Toxins 2010, 2, 2428-2466. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins2102428

AMA Style

Yadav VR, Prasad S, Sung B, Kannappan R, Aggarwal BB. Targeting Inflammatory Pathways by Triterpenoids for Prevention and Treatment of Cancer. Toxins. 2010; 2(10):2428-2466. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins2102428

Chicago/Turabian Style

Yadav, Vivek R., Sahdeo Prasad, Bokyung Sung, Ramaswamy Kannappan, and Bharat B. Aggarwal. 2010. "Targeting Inflammatory Pathways by Triterpenoids for Prevention and Treatment of Cancer" Toxins 2, no. 10: 2428-2466. https://0-doi-org.brum.beds.ac.uk/10.3390/toxins2102428

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