Combinatorial antitumor effect of HDACs and the PI3K-Akt-mTOR pathway inhibition in a Pten deficient model of prostate cancer
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Leigh Ellis1,2, ShengYu Ku1,3, Swathi Ramakrishnan1,3, Elena Lasorsa1,2, Gizzou Azabdaftari1,4, Alejandro Godoy5,7, and Roberto Pili1,6
1 Genitourinary Program, Roswell Park Cancer Institute, Buffalo NY
2 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo NY
3 Department of Cancer Prevention and Pathology, Roswell Park Cancer Institute, Buffalo NY
4 Department of Pathology, Roswell Park Cancer Institute, Buffalo NY
5 Department of Urology, Roswell Park Cancer Institute, Buffalo NY
6 Department of Medicine. Roswell Park Cancer Institute, Buffalo NY
7 Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile.
Leigh Ellis, email:
Roberto Pili, email:
Keywords: Prostate cancer, BEZ235, panobinostat, DNA damage, ATM
Received: August 21, 2013 Accepted: September 25, 2013 Published: September 27, 2013
Increased expression of histone deacetylases (HDACs) and activation of the PI3K-Akt-mTORC1 pathway are common aberrations in prostate cancer (PCa). For this reason, inhibition of such targets is an exciting avenue for the development of novel therapeutic strategies to treat patients with advanced PCa. Previous reports demonstrated that HDAC inhibitors (HDACi) increases DNA damage and induce greater apoptosis in PCa cell lines that express androgen receptor (AR). In this study we utilized the AR negative PCa cell line and observed that re-expression of AR (PC3-AR) results in greater levels of apoptosis when treated with the pan-DACi, panobinostat (PAN). PAN mediated apoptosis in PC3 and PC3-AR cells was associated with increased levels of double strand DNA breaks, indicated by p-ɣH2AX. Further, PAN treatment in PC3-AR cells resulted in moderate attenuation of the ATM-Akt-ERK DNA damage response pathway. For this reason, we combined PAN with the dual PI3K-mTOR inhibitor, BEZ235. Combination of PAN with BEZ235 resulted in significant attenuation of the DNA damage repair protein ATM and significantly increased anti-tumor activity compared to each single treatment. Overall, superior anti-tumor activity with combination of PAN with BEZ235 was independent of AR status. These findings suggest that this therapeutic strategy should be further developed in clinical trials.
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