Title

Preclinical characterization of mitochondria-targeted small molecule hsp90 inhibitors, gamitrinibs, in advanced prostate cancer

UMMS Affiliation

Department of Cell Biology; Department of Cancer Biology

Publication Date

2010-09-30

Document Type

Article

Subjects

Prostatic Neoplasms; HSP90 Heat-Shock Proteins; Mitochondria

Disciplines

Cell Biology

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.

DOI of Published Version

10.1158/1078-0432.CCR-10-1818

Source

Clin Cancer Res. 2010 Oct 1;16(19):4779-88. Epub 2010 Sep 28. Link to article on publisher's site

Journal/Book/Conference Title

Clinical cancer research : an official journal of the American Association for Cancer Research

Related Resources

Link to Article in PubMed

PubMed ID

20876793

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