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Hsp90 inhibitors as novel cancer chemotherapeutic agents
1Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, 9610 Medical Center Drive, Suite 300, Rockville, MD 20850, USA. len@helix.nih.gov
Abstract:
Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for the stability and function of multiple mutated, chimeric and over-expressed signaling proteins that promote the growth and/or survival of cancer cells. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, ErbB2 and hypoxia-inducible factor 1 alpha (HIF-1 alpha). Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins, and they have shown promising antitumor activity in preclinical model systems. One Hsp90 inhibitor, 17-allylaminogeldanamycin (17AAG), is currently in phase I clinical trial. Because of the chemoprotective activity of several proteins that are Hsp90 clients, the combination of an Hsp90 inhibitor with a standard chemotherapeutic agent could dramatically increase the in vivo efficacy of the therapeutic agent.
Insights
Heat shock protein 90 (Hsp90) inhibitors target cancer cell survival proteins. Combining Hsp90 inhibitors with chemotherapy may enhance antitumor efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Heat shock protein 90 (Hsp90) is a molecular chaperone essential for the stability and function of numerous signaling proteins that drive cancer cell growth and survival.
- Key Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, ErbB2, and hypoxia-inducible factor 1 alpha (HIF-1 alpha).
Purpose of the Study:
- To investigate the therapeutic potential of Hsp90 inhibitors in cancer treatment.
- To explore the combination of Hsp90 inhibitors with standard chemotherapeutic agents for enhanced efficacy.
Main Methods:
- Hsp90 inhibitors interact with a single molecular target, leading to the destabilization and degradation of Hsp90 client proteins.
- Preclinical model systems were utilized to assess the antitumor activity of Hsp90 inhibitors.
- One Hsp90 inhibitor, 17-allylaminogeldanamycin (17AAG), is undergoing phase I clinical trials.
Main Results:
- Hsp90 inhibitors demonstrated promising antitumor activity in preclinical models.
- The chemoprotective roles of several Hsp90 client proteins suggest potential for combination therapies.
Conclusions:
- Hsp90 inhibitors represent a targeted approach to destabilize key cancer-promoting proteins.
- Combining Hsp90 inhibitors with conventional chemotherapy could significantly improve therapeutic outcomes in cancer patients.