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

Kang, B. H.; Tavecchio, M LU ; Goel, H L; Hsieh, C-C; Garlick, David S; Raskett, C M; Lian, J B; Stein, G S; Languino, Lucia R and Altieri, Dario C (2011) In British Journal of Cancer 104(4). p.34-629
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... (More)

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.

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Contribution to journal
publication status
published
keywords
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, Journal Article, Research Support, N.I.H., Extramural
in
British Journal of Cancer
volume
104
issue
4
pages
6 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:79951673830
ISSN
1532-1827
DOI
10.1038/bjc.2011.9
language
English
LU publication?
no
id
2cfdf5c0-83a0-4d34-9ca1-e26a1f9afaea
date added to LUP
2017-03-07 09:11:39
date last changed
2017-07-30 05:22:46
@article{2cfdf5c0-83a0-4d34-9ca1-e26a1f9afaea,
  abstract     = {<p>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.</p><p>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.</p><p>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.</p><p>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.</p>},
  author       = {Kang, B. H. and Tavecchio, M and Goel, H L and Hsieh, C-C and Garlick, David S and Raskett, C M and Lian, J B and Stein, G S and Languino, Lucia R and Altieri, Dario C},
  issn         = {1532-1827},
  keyword      = {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,Journal Article,Research Support, N.I.H., Extramural},
  language     = {eng},
  month        = {02},
  number       = {4},
  pages        = {34--629},
  publisher    = {Nature Publishing Group},
  series       = {British Journal of Cancer},
  title        = {Targeted inhibition of mitochondrial Hsp90 suppresses localised and metastatic prostate cancer growth in a genetic mouse model of disease},
  url          = {http://dx.doi.org/10.1038/bjc.2011.9},
  volume       = {104},
  year         = {2011},
}