Abstract
In their role as molecular chaperones, heat shock proteins serve as central integrators of protein homeostasis within cells. As part of this function, they guide the folding, assembly, intracellular disposition and proteolytic turnover of many key regulators of cell growth, differentiation and survival. Not surprisingly then, heat shock proteins are over expressed in many types of cancer, and induction of the stress response may actually be required for cells to tolerate the genetic disarray characteristic of malignant transformation. Regulation of heat shock protein levels via the stress response is complex, but recent data indicate that the molecular chaperone Hsp90 plays a key role. Specifically, Hsp90 inhibitors alter the multi-chaperone complexes associated with Heat Shock Factor 1 (HSF1), the dominant transcription factor controlling induction of the stress response, and stimulate HSF1-activated heat shock gene expression. Induction of this heat shock response has now emerged as an important consideration in the further clinical development of Hsp90 inhibitors for several reasons. First, tumors in which the stress response is compromised appear particularly sensitive to Hsp90 inhibition. Second, induction of the stress response by Hsp90 inhibitors provides a sensitive pharmacodynamic endpoint with which to monitor drug action in individual patients. Third, Hsp90 inhibitors display important therapeutic interactions with both conventional DNA-targeted chemotherapeutics and newer molecularly targeted agents. These interactions are, at least in part, due to modulation of the stress response by these drugs. Lastly, stress response induction by Hsp90 inhibitors may have therapeutic benefits in non-neoplastic disorders such as heart disease, stroke and neurodegenerative diseases. These benefits are just beginning to be explored.
Keywords: Hsp90, multi-chaperone, pharmacodynamic, heat shock gene
Current Cancer Drug Targets
Title: The Stress Response: Implications for the Clinical Development of Hsp90 Inhibitors
Volume: 3 Issue: 5
Author(s): Luke Whitesell, Rochelle Bagatell and Ryan Falsey
Affiliation:
Keywords: Hsp90, multi-chaperone, pharmacodynamic, heat shock gene
Abstract: In their role as molecular chaperones, heat shock proteins serve as central integrators of protein homeostasis within cells. As part of this function, they guide the folding, assembly, intracellular disposition and proteolytic turnover of many key regulators of cell growth, differentiation and survival. Not surprisingly then, heat shock proteins are over expressed in many types of cancer, and induction of the stress response may actually be required for cells to tolerate the genetic disarray characteristic of malignant transformation. Regulation of heat shock protein levels via the stress response is complex, but recent data indicate that the molecular chaperone Hsp90 plays a key role. Specifically, Hsp90 inhibitors alter the multi-chaperone complexes associated with Heat Shock Factor 1 (HSF1), the dominant transcription factor controlling induction of the stress response, and stimulate HSF1-activated heat shock gene expression. Induction of this heat shock response has now emerged as an important consideration in the further clinical development of Hsp90 inhibitors for several reasons. First, tumors in which the stress response is compromised appear particularly sensitive to Hsp90 inhibition. Second, induction of the stress response by Hsp90 inhibitors provides a sensitive pharmacodynamic endpoint with which to monitor drug action in individual patients. Third, Hsp90 inhibitors display important therapeutic interactions with both conventional DNA-targeted chemotherapeutics and newer molecularly targeted agents. These interactions are, at least in part, due to modulation of the stress response by these drugs. Lastly, stress response induction by Hsp90 inhibitors may have therapeutic benefits in non-neoplastic disorders such as heart disease, stroke and neurodegenerative diseases. These benefits are just beginning to be explored.
Export Options
About this article
Cite this article as:
Whitesell Luke, Bagatell Rochelle and Falsey Ryan, The Stress Response: Implications for the Clinical Development of Hsp90 Inhibitors, Current Cancer Drug Targets 2003; 3 (5) . https://dx.doi.org/10.2174/1568009033481787
DOI https://dx.doi.org/10.2174/1568009033481787 |
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
-
Living Heart Valve and Small-Diameter Artery Substitutes - An Emerging Field for Intellectual Property Development
Recent Patents on Biotechnology Recent Patents on Diacylglycerol Production and Applications
Recent Patents on Chemical Engineering Cardiovascular Adverse Effects of Anti-Inflammatory Drugs
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Angiotensin Converting Enzyme-2: A Doorway for SARS-CoV-2
Coronaviruses Dyslipidaemia Related to Insulin Resistance and Cardiovascular Disease in South Asian and West African Populations
Current Pharmaceutical Design The Role of Orexin System in Antipsychotics Induced Weight Gain
Current Psychiatry Reviews Editorial (Should Chronic Kidney Disease be Considered as a Coronary Heart Disease Equivalent?)
Current Vascular Pharmacology A Recent Update on the Effects of Omega-3 Fatty Acids in Alzheimer’s Disease
Current Clinical Pharmacology Hematoma Expansion: Clinical and Molecular Predictors and Corresponding Pharmacological Treatment
Current Drug Targets New Insights into the Mechanisms Underlying Vascular and Cardiac Effects of Urocortin
Current Vascular Pharmacology Potential Benefits and Limits of Psychopharmacological Therapies in Pervasive Developmental Disorders
Current Clinical Pharmacology What’s Age Got to do with it? A Review of Contemporary Revascularization in the Elderly
Current Cardiology Reviews Guggulsterone for Chemoprevention of Cancer
Current Pharmaceutical Design Statins Attenuate Fibrotic Manifestations of Cardiac Tissue Damage
Current Molecular Pharmacology NAD in Skin: Therapeutic Approaches for Niacin
Current Pharmaceutical Design Colchicine: A Review on Chemical Structure and Clinical Usage
Infectious Disorders - Drug Targets Hypertension: Basics Concepts and the Evolving Role of Novel Treatments
Current Hypertension Reviews Cardiovascular Manifestations of COVID-19
Current Cardiology Reviews Von Willebrand Factor and Thrombosis: Risk Factor, Actor and Pharmacological Target
Current Vascular Pharmacology Vitamin D and Vitamin D Receptor Activators in Treatment of Hypertension and Cardiovascular Disease
Cardiovascular & Hematological Disorders-Drug Targets