esearch cer Therapy : Preclinical clinical Characterization of Mitochondria - Targeted Small ecule Hsp 90 Inhibitors , Gamitrinibs , in Advanced R state Cancer

ownloade pose: This study aimed to characterize the preclinical activity of the first class of combinatorial, hondria-targeted, small molecule heat shock protein-90 (Hsp90) inhibitors, gamitrinibs, in models mone-refractory, drug-resistant, localized, and bone metastatic prostate cancer in vivo. erimental Design: Mitochondrial permeability transition, apoptosis, and changes in metabolic acwere examined by time-lapse videomicroscopy, multiparametric flow cytometry, MTT, and analysis lated mitochondria. Drug-resistant prostate cancer cells were generated by chronic exposure of ne-refractory PC3 cells to the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG). The effect itrinibs on s.c. or intratibial prostate cancer growth was studied in xenograft models. Bone metatumor growth and bone parameters were quantified by micro–computed tomography imaging. ults: In the NCI 60-cell line screening, gamitrinibs were active against all tumor cell types tested, ficiently killed metastatic, hormone-refractory, and multidrug-resistant prostate cancer cells characby overexpression of the ATP binding cassette transporter P-glycoprotein. Mechanistically, gamis, but not 17-AAG, induced acute mitochondrial dysfunction in prostate cancer cells with loss of elle membrane potential, release of cytochrome c, and caspase activity, independently of prootic Bcl-2 proteins Bax and Bak. Systemic administration of gamitrinibs to mice was well tolerated, hibited s.c. or bone metastatic prostate cancer growth in vivo. and in Conclusions: Gamitrinibs have preclinical activity and favorable safety in models of drug-resistant and bone metastatic prostate cancer in vivo. Clin Cancer Res; 16(19); 4779–88. ©2010 AACR.