Modulation of Hsp90 function by ansamycins sensitizes breast cancer cells to chemotherapy-induced apoptosis in an RB- and schedule-dependent manner. See: E. A. Sausville, Combining cytotoxics and 17-allylamino, 17-demethoxygeldanamycin: sequence and tumor biology matters, Clin. Cancer Res., 7: 2155-2158, 2001.

Abstract

17-allyl-aminogeldanamycin (17-AAG) is an ansamycin antibiotic that binds to a highly conserved pocket in the Hsp90 chaperone protein and inhibits its function. Hsp90 is required for the refolding of proteins during cellular stress and the conformational maturation of certain signaling proteins. 17-AAG has antitumor activity in cell culture and animal xenograft models and is currently in clinical trial. It causes an RB-dependent G(1) arrest, differentiation, and apoptosis. RB-negative cells arrest in mitosis and undergo apoptosis. Hsp90 plays an important role in the cellular response to environmental stress. Therefore, we tested whether the regulation of Hsp90 function by 17-AAG could sensitize cells to cytotoxic agents. 17-AAG sensitized tumor cells to Taxol and doxorubicin. Taxanes cause growth arrest in mitosis and apoptosis. The addition of 17-AAG to cells after exposure to Taxol significantly increased both the activation of caspases 9 and 3 and apoptosis. In cells with intact RB, exposure to 17-AAG before Taxol resulted in G(1) arrest and abrogated apoptosis. Schedule dependence was not seen in cells with mutated RB, because both agents blocked cells in mitosis. Schedule- or RB-dependence was also not observed when cells were treated with 17-AAG and doxorubicin, a DNA-intercalating agent that acts on different phases of the cell cycle. These findings suggest that inhibition of Hsp90 function by 17-AAG enhances the apoptotic effects of cytotoxic agents. The sequence of drug administration and the RB status significantly influence efficacy.

• Authors: P N Münster, A Basso, D Solit, L Norton, N Rosen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 7 Issue 8 Pg. 2228-36 (Aug 2001) ISSN: 1078-0432 [Print] United States
• PMID: 11489796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Bacterial Agents
• Antineoplastic Agents, Phytogenic
• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Retinoblastoma Protein
• Rifabutin
• tanespimycin
• Doxorubicin
• CASP3 protein, human
• CASP9 protein, human
• Caspase 3
• Caspase 9
• Caspases
• Paclitaxel

Topics

• Anti-Bacterial Agents (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Benzoquinones
• Breast Neoplasms (drug therapy, pathology, physiopathology)
• Caspase 3
• Caspase 9
• Caspases (drug effects, metabolism)
• Cell Division (drug effects)
• Dose-Response Relationship, Drug
• Doxorubicin (pharmacology)
• Drug Synergism
• Enzyme Activation (drug effects)
• HSP90 Heat-Shock Proteins (drug effects, physiology)
• Humans
• Lactams, Macrocyclic
• Mitosis (physiology)
• Paclitaxel (pharmacology)
• Retinoblastoma Protein (genetics, physiology)
• Rifabutin (analogs & derivatives, pharmacology)
• Time Factors
• Tumor Cells, Cultured (drug effects)