Abstract
Radicicol, a macrocyclic antibiotic produced by fungi, was originally isolated many years ago, and was described as tyrosine kinase inhibitor. We also rediscovered radicicol as an inhibitor of signal transduction of oncogene products, such as K-ras and v-Src, using yeast and mammalian cell-based assays. In a study of mechanisms of action, it was revealed that radicicol depletes the Hsp90 client signaling molecules in cells, and thus inhibit the signal transduction pathway. In addition, direct binding of radicicol to the Nterminal ATP / ADP binding site of Hsp90 was shown, and thus radicicol has been recognized as a structurally unique antibiotic that binds and inhibits the molecular chaperone Hsp90. Although radicicol itself has little or no activity in animals because of instability in animals, its oxime derivatives showed potent antitumor activities against human tumor xenograft models. Hsp90 client proteins were depleted and apoptosis was induced in the tumor specimen treated with radicicol oxime derivatives. Taken together, these results suggest that the antitumor activity of radicicol oxime derivatives is mediated by binding to Hsp90 and destabilization of Hsp90 client proteins in the tumor. Among Hsp90 clients, we focused on ErbB2 and Bcr-Abl as examples of important targets of Hsp90 inhibitors. Radicicol oxime showed potent antitumor activity against ER negative / ErbB2 overexpressing breast cancer and Bcr-Abl expressing CML. Putative mechanisms of action and future directions of radicicol oxime against these kinds of tumor are discussed.
Keywords: macrocyclic, ErbB2, Hsp90, Bcr-Abl, Radicicol Analogues
Current Cancer Drug Targets
Title: Development of Radicicol Analogues
Volume: 3 Issue: 5
Author(s): Shiro Soga, Yukimasa Shiotsu, Shiro Akinaga and Sreenath V. Sharma
Affiliation:
Keywords: macrocyclic, ErbB2, Hsp90, Bcr-Abl, Radicicol Analogues
Abstract: Radicicol, a macrocyclic antibiotic produced by fungi, was originally isolated many years ago, and was described as tyrosine kinase inhibitor. We also rediscovered radicicol as an inhibitor of signal transduction of oncogene products, such as K-ras and v-Src, using yeast and mammalian cell-based assays. In a study of mechanisms of action, it was revealed that radicicol depletes the Hsp90 client signaling molecules in cells, and thus inhibit the signal transduction pathway. In addition, direct binding of radicicol to the Nterminal ATP / ADP binding site of Hsp90 was shown, and thus radicicol has been recognized as a structurally unique antibiotic that binds and inhibits the molecular chaperone Hsp90. Although radicicol itself has little or no activity in animals because of instability in animals, its oxime derivatives showed potent antitumor activities against human tumor xenograft models. Hsp90 client proteins were depleted and apoptosis was induced in the tumor specimen treated with radicicol oxime derivatives. Taken together, these results suggest that the antitumor activity of radicicol oxime derivatives is mediated by binding to Hsp90 and destabilization of Hsp90 client proteins in the tumor. Among Hsp90 clients, we focused on ErbB2 and Bcr-Abl as examples of important targets of Hsp90 inhibitors. Radicicol oxime showed potent antitumor activity against ER negative / ErbB2 overexpressing breast cancer and Bcr-Abl expressing CML. Putative mechanisms of action and future directions of radicicol oxime against these kinds of tumor are discussed.
Export Options
About this article
Cite this article as:
Soga Shiro, Shiotsu Yukimasa, Akinaga Shiro and Sharma V. Sreenath, Development of Radicicol Analogues, Current Cancer Drug Targets 2003; 3 (5) . https://dx.doi.org/10.2174/1568009033481859
DOI https://dx.doi.org/10.2174/1568009033481859 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...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
-
Antioxidant Properties of Crocus Sativus L. and Its Constituents and Relevance to Neurodegenerative Diseases; Focus on Alzheimer’s and Parkinson’s Disease
Current Neuropharmacology Hypothalamic Insulin-Sensitizing Effect of Exenatide in Dietary Induced Rat Model of Obesity
Current Drug Therapy Deciphering the Neuroprotective Role of Glucagon-like Peptide-1 Agonists in Diabetic Neuropathy: Current Perspective and Future Directions
Current Protein & Peptide Science Targeted Therapy for Advanced Prostate Cancer: Inhibition of the PI3K/Akt/mTOR Pathway
Current Cancer Drug Targets New Features in the Treatment of Androgen-Independent Prostate Cancer
Current Pharmaceutical Design Unlocking the Molecular Mechanisms of DNA Repair and Platinum Drug Resistance in Cancer Chemotherapy
Current Drug Therapy Clinical and Pharmacological Aspects of Inflammatory Demyelinating Diseases in Childhood: An Update
Current Neuropharmacology Targeting Cancer Cells with Photoactive Silica Nanoparticles
Current Pharmaceutical Design Discovery of 8-methoxypyrazino[1,2-a]indole as a New Potent Antiproliferative Agent Against Human Leukemia K562 Cells. A Structure-Activity Relationship Study
Letters in Drug Design & Discovery New Vascular Disrupting Agents in Upper Gastrointestinal Malignancies
Current Medicinal Chemistry Regulation of ABC Transporter Function Via Phosphorylation by Protein Kinases
Current Pharmaceutical Biotechnology Metformin, A New Era for an Old Drug in the Treatment of Immune Mediated Disease?
Current Drug Targets Carbon Nanotubes: An Emerging Drug Delivery Carrier in Cancer Therapeutics
Current Drug Delivery Endogenous Acetylcholine Controls the Severity of Polymicrobial Sepsisassociated Inflammatory Response in Mice
Current Neurovascular Research Editorial [Hot Topic Intracellular Calcium Signaling: Holding the Balance between Health and Disease Guest Editor: Luca Munaron]
Current Medicinal Chemistry An Optimized Approach for Breast Cancer Classification for Histopathological Images Based on Hybrid Feature Set
Current Medical Imaging IAPs as a Target for Anticancer Therapy
Current Cancer Drug Targets Targeting Different Pathways Using Novel Combination Therapy in Triple Negative Breast Cancer
Current Cancer Drug Targets Non-Analgesic Effects of Opioids: Opioid-induced Nausea and Vomiting: Mechanisms and Strategies for their Limitation
Current Pharmaceutical Design Hollow Inorganic Nanoparticles as Efficient Carriers for siRNA Delivery: A Comprehensive Review
Current Pharmaceutical Design