The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer
R Diaz (1,5), PA Nguewa (1,5), JA Diaz-Gonzalez (2), E Hamel (3), O Gonzalez-Moreno (1), R Catena (1), D Serrano (1), M Redrado (1), D Sherris (4) and A Calvo (1)
(1)Division of Oncology, Center for Applied Medical Research (CIMA). University of Navarra, Pamplona, Spain
(2) Department of Oncology, Clinica Universitaria, University of Navarra, Pamplona, Spain
(3) Division of Cancer Treatment and Diagnosis, Toxicology and Pharmacology Branch, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA
(4) Paloma Pharmaceuticals, Jamaica Plain, MA, USA
Magazine: British Journal of Cancer
Date: Mar 24, 2009Radiation Oncology
Radiotherapy (RT) is a common treatment for localised prostate cancer, but can cause important side effects.
The therapeutic efficacy of RT can be enhanced by pharmacological compounds that target specific pathways involved in cell survival. This would elicit a similar therapeutic response using lower doses of RT and, in turn, reducing side effects. This study describes the antitumour activity of the novel Akt inhibitor 8-(1-Hydroxy-ethyl)-2-methoxy-3-(4-methoxy-benzyloxy)-benzo[c]chromen-6-one (Palomid 529 or P529) as well as its ability to decrease radiation-activated phospho-Akt (p-Akt) signalling in a prostate cancer model. P529 showed a potent antiproliferative activity in the NCI-60 cell lines panel, with growth inhibitory 50 (GI50) <35 microM.
In addition, P529 significantly enhanced the antiproliferative effect of radiation in prostate cancer cells (PC-3). Analysis of signalling pathways targeted by P529 exhibited a decrease in p-Akt, VEGF, MMP-2, MMP-9, and Id-1 levels after radiation treatment. Moreover, the Bcl-2/Bax ratio was also reduced. Treatment of PC-3 tumour-bearing mice with 20 mg kg(-1) P529 or 6 Gy radiation dose decreased tumour size by 42.9 and 53%, respectively. Combination of both treatments resulted in 77.4% tumour shrinkage. Decreased tumour growth was due to reduced proliferation and increased apoptosis (as assessed by PCNA and caspase-3 immunostaining).
Our results show the antitumour efficacy of P529 alone, and as a radiosensitiser, and suggest that this compound could be used in the future to treat human prostate cancer.
CITATION Br J Cancer. 2009 Mar 24;100(6):932-40
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