Targeted inhibition of mitochondrial Hsp90 suppresses localised and metastatic prostate cancer growth in a genetic mouse model of disease
Authors
Kang, Byoung H.Tavecchio, M.
Goel, Hira Lal
Hsieh, Chung-Cheng
Garlick, David S.
Raskett, Christopher M.
Lian, Jane B.
Stein, Gary S.
Languino, Lucia R.
Altieri, Dario C.
Document Type
Journal ArticlePublication Date
2011-02-15Keywords
AdenocarcinomaAnimals
Antineoplastic Agents
Cell Proliferation
Cells, Cultured
Disease Models, Animal
Disease Progression
Drug Evaluation, Preclinical
Female
Genetic Predisposition to Disease
Guanidines
HSP90 Heat-Shock Proteins
Lactams, Macrocyclic
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria
Molecular Targeted Therapy
Neoplasm Metastasis
Prostatic Intraepithelial Neoplasia
Prostatic Neoplasms
Cancer Biology
Cell Biology
Metadata
Show full item recordAbstract
BACKGROUND: The molecular chaperone heat shock protein-90 (Hsp90) is a promising cancer drug target, but current Hsp90-based therapy has so far shown limited activity in the clinic. METHODS: We tested the efficacy of a novel mitochondrial-targeted, small-molecule Hsp90 inhibitor, Gamitrinib (GA mitochondrial matrix inhibitor), in the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. The TRAMP mice receiving 3-week or 5-week systemic treatment with Gamitrinib were evaluated for localised or metastatic prostate cancer, prostatic intraepithelial neoplasia (PIN) or localised inflammation using magnetic resonance imaging, histology and immunohistochemistry. Treatment safety was assessed histologically in organs collected at the end of treatment. The effect of Gamitrinib on mitochondrial dysfunction was studied in RM1 cells isolated from TRAMP tumours. RESULTS: Systemic administration of Gamitrinib to TRAMP mice inhibited the formation of localised prostate tumours of neuroendocrine or adenocarcinoma origin, as well as metastatic prostate cancer to abdominal lymph nodes and liver. The Gamitrinib treatment had no effect on PIN or prostatic inflammation, and caused no significant animal weight loss or organ toxicity. Mechanistically, Gamitrinib triggered acute mitochondrial dysfunction in RM1 cells, with loss of organelle inner membrane potential and release of cytochrome-c in the cytosol. CONCLUSIONS: The Gamitrinib has pre-clinical activity and favourable tolerability in a genetic model of localised and metastatic prostate cancer in immunocompetent mice. Selective targeting of mitochondrial Hsp90 could provide novel molecular therapy for patients with advanced prostate cancer.Source
Br J Cancer. 2011 Feb 15;104(4):629-34. Epub 2011 Feb 1. Link to article on publisher's siteDOI
10.1038/bjc.2011.9Permanent Link to this Item
http://hdl.handle.net/20.500.14038/49586PubMed ID
21285984Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/bjc.2011.9