Heat-shock protein 90 inhibitors in antineoplastic therapy: is it all wrapped up?
Heat-shock protein (Hsp)-90 belongs to the class of molecular chaperone proteins that are capable of sensing cellular stress. Although Hsp90 is essential for viability, the pharmacological inhibition of this chaperone has emerged as an attractive means to inhibit tumorigenesis. This phenomenon is due to a unique property of Hsp90; its 'client proteins' are universally involved in signal transduction pathways commonly dysregulated in, and contributing to, cancer. The natural product geldanamycin, a potent ansamycin Hsp90 inhibitor, has served as a lead compound for the development of several derivatives that are currently undergoing clinical trials. Inhibition of Hsp90 with geldanamycin simultaneously depletes Hsp90-associated clients and impairs numerous signalling cascades that depend on chaperone function. Importantly, tumour cells are exquisitely sensitive to Hsp90 inhibition, lending credence to the feasibility of selectively targeting cancer tissue via the pharmacological modulation of Hsp90 function. Even more remarkably, Hsp90 inhibitors sensitise tumour cells to the cytotoxic effects of a variety of standard therapeutics, and thus, they are likely to have broad utility in combination therapy. Although these are promising developments, much remains to be discovered about client-chaperone biology and the tumour-specific effects of Hsp90 blockade. This information is required to fully grasp the multi-faceted roles of Hsp90 in cancer biology towards the goal of optimising the use of these agents in the clinic. Elucidation of these nuances will undoubtedly lead to better targeting of relevant oncogenic pathways and translate into the development of more effective anticancer regimens.
Isaacs
Jennifer S
JS
Urologic Oncology Branch, Center for Cancer Research, NCI, National Institutes of Health, Rockville, MD, USA. isaacsj@mail.nih.gov
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000639:trends; D015507:Drugs, Investigational / Q000627:therapeutic use*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism
D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D018841:HSP90 Heat-Shock Proteins