eScholarship@UMMS

Title

Targeted inhibition of mitochondrial Hsp90 suppresses localised and metastatic prostate cancer growth in a genetic mouse model of disease

Authors

Byoung H. Kang, Wistar Institute Cancer Center
M. Tavecchio, Wistar Institute Cancer Center
Hira Lal Goel, University of Massachusetts Medical SchoolFollow
Chung-Cheng Hsieh, University of Massachusetts Medical SchoolFollow
David S. Garlick, University of Massachusetts Medical SchoolFollow
Christopher M. Raskett, University of Massachusetts Medical SchoolFollow
Jane B. Lian, University of Massachusetts Medical SchoolFollow
Gary S. Stein, University of Massachusetts Medical SchoolFollow
Lucia R. Languino, Thomas Jefferson University
Dario C. Altieri, Wistar Institute Cancer Center

UMMS Affiliation

Department of Cancer Biology; Department of Cell Biology

Publication Date

2011-02-15

Document Type

Article

Subjects

Adenocarcinoma; Animals; 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

Disciplines

Cancer Biology | Cell Biology

Abstract

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.

DOI of Published Version

10.1038/bjc.2011.9

Source

Br J Cancer. 2011 Feb 15;104(4):629-34. Epub 2011 Feb 1. Link to article on publisher's site

Journal/Book/Conference Title

British journal of cancer

Related Resources

Link to Article in PubMed

PubMed ID

21285984

Repository Citation

Kang BH, Tavecchio M, Goel HL, Hsieh C, Garlick DS, Raskett CM, Lian JB, Stein GS, Languino LR, Altieri DC. (2011). Targeted inhibition of mitochondrial Hsp90 suppresses localised and metastatic prostate cancer growth in a genetic mouse model of disease. Stein, Stein, Lian, vanWijnen Lab Publications. https://doi.org/10.1038/bjc.2011.9. Retrieved from https://escholarship.umassmed.edu/stein/256