Abstract
Microcystin-LR and nodularin, along with okadaic acid, are potent inhibitors of protein phosphatases 1 and 2A (PP1 and PP2A). The mechanisms of action of microcystin-LR and nodularin in the liver and that of okadaic acid, a potent tumor promoter on mouse skin, have attracted the attention of the scientists. This paper reviews several topics: new inhibitors of PP1 and PP2A with new chemical structures, structure-function relationships for both receptor binding and inhibition of protein phosphatases, the crystal structure of PP1 or PP2A – toxin complex, induction of gene expression and apoptosis. These subjects were studied by using in vitro and in vivo experimental systems. Two-stage carcinogenesis experiments with microcystin-LR and nodularin for the first time demonstrated that microcystin- LR is a new tumor promoter in rat liver initiated with diethylnitrosamine (DEN), and that nodularin is a potent tumor promoter associated with weak initiating activity in rat liver initiated with DEN. A working group of WHO (IARC) concluded that microcystin-LR is “possibly carcinogenic to humans” and that nodularin is “not classifiable as to carcinogenicity”. Our studies revealed that chemical tumor promoters are inducers of TNF-α in the cells of target tissues and that TNF-α is an endogenous tumor promoter. This advance in carcinogenesis made it possible to look for the link between chemical tumor promoters and endogenous tumor promoters, such as TNF-α and IL-1. The carcinogenic features of TNF-α are described in this review, and the TNF-α inducing protein (Tipα) of elicobacter pylori genome is presented as an example of a tumor promoter of human stomach cancer development.
Keywords: Apparent activation of protein kinases, microcystin-LR, nodularin, liver carcinogenesis, okadaic acid, protein phosphatases 1 and 2A, tumor necrosis factor, tumor promotion, IARC, TNF, DEN
Anti-Cancer Agents in Medicinal Chemistry
Title: Tumor Promoters - Microcystin-LR, Nodularin and TNF-α and Human Cancer Development
Volume: 11 Issue: 1
Author(s): Hirota Fujiki and Masami Suganuma
Affiliation:
Keywords: Apparent activation of protein kinases, microcystin-LR, nodularin, liver carcinogenesis, okadaic acid, protein phosphatases 1 and 2A, tumor necrosis factor, tumor promotion, IARC, TNF, DEN
Abstract: Microcystin-LR and nodularin, along with okadaic acid, are potent inhibitors of protein phosphatases 1 and 2A (PP1 and PP2A). The mechanisms of action of microcystin-LR and nodularin in the liver and that of okadaic acid, a potent tumor promoter on mouse skin, have attracted the attention of the scientists. This paper reviews several topics: new inhibitors of PP1 and PP2A with new chemical structures, structure-function relationships for both receptor binding and inhibition of protein phosphatases, the crystal structure of PP1 or PP2A – toxin complex, induction of gene expression and apoptosis. These subjects were studied by using in vitro and in vivo experimental systems. Two-stage carcinogenesis experiments with microcystin-LR and nodularin for the first time demonstrated that microcystin- LR is a new tumor promoter in rat liver initiated with diethylnitrosamine (DEN), and that nodularin is a potent tumor promoter associated with weak initiating activity in rat liver initiated with DEN. A working group of WHO (IARC) concluded that microcystin-LR is “possibly carcinogenic to humans” and that nodularin is “not classifiable as to carcinogenicity”. Our studies revealed that chemical tumor promoters are inducers of TNF-α in the cells of target tissues and that TNF-α is an endogenous tumor promoter. This advance in carcinogenesis made it possible to look for the link between chemical tumor promoters and endogenous tumor promoters, such as TNF-α and IL-1. The carcinogenic features of TNF-α are described in this review, and the TNF-α inducing protein (Tipα) of elicobacter pylori genome is presented as an example of a tumor promoter of human stomach cancer development.
Export Options
About this article
Cite this article as:
Fujiki Hirota and Suganuma Masami, Tumor Promoters - Microcystin-LR, Nodularin and TNF-α and Human Cancer Development, Anti-Cancer Agents in Medicinal Chemistry 2011; 11 (1) . https://dx.doi.org/10.2174/187152011794941163
DOI https://dx.doi.org/10.2174/187152011794941163 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
The Clinical Characteristics and Survival Profiles of Wilms Tumor in the United Arab Emirates: A Single-center Retrospective Analysis
New Emirates Medical Journal The Targets of Curcumin
Current Drug Targets Hyperglycemia, Hypoglycemia and Dementia: Role of Mitochondria and Uncoupling Proteins
Current Molecular Medicine Combating Protein Misfolding and Aggregation by Intracellular Antibodies
Current Molecular Medicine Roles of EGFR, PI3K, AKT, and mTOR in Heavy Metal-Induced Cancer
Current Cancer Drug Targets Therapeutic Targeting of Malignant Glioma
Anti-Cancer Agents in Medicinal Chemistry Chlorogenic Acid and Mental Diseases: From Chemistry to Medicine
Current Neuropharmacology An Effective HIV Vaccine: A Combination of Humoral and Cellular Immunity?
Current HIV Research Influence of Trishomocubanes on Sigma Receptor Binding of N-(1-Benzylpiperidin- 4-yl)-4-[123I]iodobenzamide In Vivo in the Rat Brain
Medicinal Chemistry Functional Role of Glycosphingolipids in Cancer
Current Medicinal Chemistry PACAP and Its Receptors Exert Pleiotropic Effects in The Nervous System by Activating Multiple Signaling Pathways
Current Protein & Peptide Science Cellular and Molecular Regulation of Inflammatory Pain, Nociception and Hyperalgesia - The Role of the Transcription Factor NF-κB as the Lynchpin Nocisensor: Hyperalgesic or Analgesic Effect?
Current Immunology Reviews (Discontinued) HLA-G - From Fetal Tolerance to a Regulatory Molecule in Inflammatory Diseases
Current Immunology Reviews (Discontinued) Interaction of Endocannabinoid Receptors with Biological Membranes
Current Medicinal Chemistry Possible Use of Autologous Stem Cell Therapies for Alzheimers Disease
Current Alzheimer Research Resveratrol and Neurodegenerative Diseases: Activation of SIRT1 as the Potential Pathway towards Neuroprotection
Current Neurovascular Research bHLH Transcription Factors Inhibitors for Cancer Therapy: General Features for In Silico Drug Design
Current Medicinal Chemistry Alteration of Isocitrate Dehydrogenase Following Acute Ischemic Injury as a Means to Improve Cellular Energetic Status in Neuroadaptation
CNS & Neurological Disorders - Drug Targets A Novel Monoclonal Antibody Against the C-terminus of β-Tubulin Recognizes Endocytic Organelles in Trypanosoma cruzi
Protein & Peptide Letters Assessing Activation States in Microglia
CNS & Neurological Disorders - Drug Targets