Geldanamycin, an ansamycin-derivative benzoquinone compound, was originally isolated as a natural product with anti-fungal activity. Later, geldanamycin was found to have anti-proliferative activity on tumor cells transformed by oncogene kinases such as v-Src. Geldanamycin neither bind nor inhibit oncogene kinases directly, but specifically binds and inhibits a major molecular chaperone, Hsp90. Hsp90 is a highly abundant and essential cytosolic protein and the expression level of Hsp90 increases by environmental stress. Hsp90 functions as a molecular chaperone by binding to various cellular proteins and supporting the proper folding, stability, and function of target proteins. The Hsp90 client proteins include a wide variety of signal-transducing proteins that regulate cell growth and differentiation, such as protein kinases and steroid hormone receptors. Hsp90 functions in an ATP-dependent manner in cooperation with other molecular chaperones such as Cdc37 and FKBP52. Geldanamycin specifically inhibits the essential ATPase activity of Hsp90. Thus, treatment of cells with geldanamycin results in inactivation, destabilization, and degradation of Hsp90 client proteins. Because Hsp90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, and oncogenesis, geldanamycin obstructs the proliferation of cancer cells and shows anti-cancer activity in experimental animals. Although difficulties with solubility and toxicity should be overcome, Hsp90 inhibitors will be potential and effective cancer chemotherapeutic drugs with a unique profile. In fact, a modified geldanamycin with lower toxicity, 17-allylaminogeldanamycin (17-AAG), has been examined in phase I clinical trials with encouraging results.
hsp90, molecular chaperone, geldanamycin, protein kinase, signal transduction, cell growth, cancer chemotherapy
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University.Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.