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DC Field | Value | Language |
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dc.citation.endPage | 4788 | - |
dc.citation.number | 19 | - |
dc.citation.startPage | 4779 | - |
dc.citation.title | CLINICAL CANCER RESEARCH | - |
dc.citation.volume | 16 | - |
dc.contributor.author | Kang, Byoung Heon | - |
dc.contributor.author | Siegelin, Markus D. | - |
dc.contributor.author | Plescia, Janet | - |
dc.contributor.author | Raskett, Christopher M. | - |
dc.contributor.author | Garlick, David S. | - |
dc.contributor.author | Dohi, Takehiko | - |
dc.contributor.author | Lian, Jane B. | - |
dc.contributor.author | Stein, Gary S. | - |
dc.contributor.author | Languino, Lucia R. | - |
dc.contributor.author | Altieri, Dario C. | - |
dc.date.accessioned | 2023-12-22T06:42:56Z | - |
dc.date.available | 2023-12-22T06:42:56Z | - |
dc.date.created | 2013-06-24 | - |
dc.date.issued | 2010-10 | - |
dc.description.abstract | 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. 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. |
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dc.identifier.bibliographicCitation | CLINICAL CANCER RESEARCH, v.16, no.19, pp.4779 - 4788 | - |
dc.identifier.doi | 10.1158/1078-0432.CCR-10-1818 | - |
dc.identifier.issn | 1078-0432 | - |
dc.identifier.scopusid | 2-s2.0-77957554723 | - |
dc.identifier.uri | https://scholarworks.unist.ac.kr/handle/201301/3343 | - |
dc.identifier.url | http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=77957554723 | - |
dc.identifier.wosid | 000282647900011 | - |
dc.language | 영어 | - |
dc.publisher | AMER ASSOC CANCER RESEARCH | - |
dc.title | Preclinical Characterization of Mitochondria-Targeted Small Molecule Hsp90 Inhibitors, Gamitrinibs, in Advanced Prostate Cancer | - |
dc.type | Article | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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