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dc.contributor.authorKang, Byoung H.
dc.contributor.authorSiegelin, Markus D.
dc.contributor.authorPlescia, Janet
dc.contributor.authorRaskett, Christopher M.
dc.contributor.authorGarlick, David S.
dc.contributor.authorDohi, Takehiko
dc.contributor.authorLian, Jane B.
dc.contributor.authorStein, Gary S.
dc.contributor.authorLanguino, Lucia R.
dc.contributor.authorAltieri, Dario C.
dc.date2022-08-11T08:10:57.000
dc.date.accessioned2022-08-23T17:26:22Z
dc.date.available2022-08-23T17:26:22Z
dc.date.issued2010-09-30
dc.date.submitted2011-01-11
dc.identifier.citationClin 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>
dc.identifier.issn1078-0432 (Linking)
dc.identifier.doi10.1158/1078-0432.CCR-10-1818
dc.identifier.pmid20876793
dc.identifier.urihttp://hdl.handle.net/20.500.14038/49621
dc.description.abstractPURPOSE: 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=20876793&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1158/1078-0432.CCR-10-1818
dc.subjectProstatic Neoplasms
dc.subjectHSP90 Heat-Shock Proteins
dc.subjectMitochondria
dc.subjectCell Biology
dc.titlePreclinical characterization of mitochondria-targeted small molecule hsp90 inhibitors, gamitrinibs, in advanced prostate cancer
dc.typeJournal Article
dc.source.journaltitleClinical cancer research : an official journal of the American Association for Cancer Research
dc.source.volume16
dc.source.issue19
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/stein/5
dc.identifier.contextkey1724045
html.description.abstract<p>PURPOSE: 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.</p> <p>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.</p> <p>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.</p> <p>CONCLUSIONS: Gamitrinibs have preclinical activity and favorable safety in models of drug-resistant and bone metastatic prostate cancer in vivo.</p>
dc.identifier.submissionpathstein/5
dc.contributor.departmentDepartment of Cancer Biology
dc.contributor.departmentDepartment of Cell Biology
dc.source.pages4779-88


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