Kang, Byoung H.Siegelin, Markus D.Plescia, JanetRaskett, Christopher MGarlick, David S.Dohi, TakehikoLian, Jane B.Stein, Gary S.Languino, Lucia R.Altieri, Dario C.2022-08-232022-08-232010-09-302011-01-11Clin Cancer Res. 2010 Oct 1;16(19):4779-88. Epub 2010 Sep 28. <a href="http://dx.doi.org/10.1158/1078-0432.CCR-10-1818">Link to article on publisher's site</a>1078-0432 (Linking)10.1158/1078-0432.CCR-10-181820876793https://hdl.handle.net/20.500.14038/49621PURPOSE: This study aimed to characterize the preclinical activity of the first class of combinatorial, mitochondria-targeted, small molecule heat shock protein-90 (Hsp90) inhibitors, gamitrinibs, in models of hormone-refractory, drug-resistant, localized, and bone metastatic prostate cancer in vivo. EXPERIMENTAL DESIGN: Mitochondrial permeability transition, apoptosis, and changes in metabolic activity were examined by time-lapse videomicroscopy, multiparametric flow cytometry, MTT, and analysis of isolated mitochondria. Drug-resistant prostate cancer cells were generated by chronic exposure of hormone-refractory PC3 cells to the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG). The effect of gamitrinibs on s.c. or intratibial prostate cancer growth was studied in xenograft models. Bone metastatic tumor growth and bone parameters were quantified by micro-computed tomography imaging. RESULTS: In the NCI 60-cell line screening, gamitrinibs were active against all tumor cell types tested, and efficiently killed metastatic, hormone-refractory, and multidrug-resistant prostate cancer cells characterized by overexpression of the ATP binding cassette transporter P-glycoprotein. Mechanistically, gamitrinibs, but not 17-AAG, induced acute mitochondrial dysfunction in prostate cancer cells with loss of organelle membrane potential, release of cytochrome c, and caspase activity, independently of proapoptotic Bcl-2 proteins Bax and Bak. Systemic administration of gamitrinibs to mice was well tolerated, and inhibited s.c. or bone metastatic prostate cancer growth in vivo. CONCLUSIONS: Gamitrinibs have preclinical activity and favorable safety in models of drug-resistant and bone metastatic prostate cancer in vivo.en-USProstatic NeoplasmsHSP90 Heat-Shock ProteinsMitochondriaCell BiologyJournal Articlehttps://escholarship.umassmed.edu/stein/51724045stein/5