Combinatorial antitumor effect of HDACs and the PI3K-Akt-mTOR pathway inhibition in a Pten deficient model of prostate cancer

Leigh Ellis, Sheng Yu Ku, Swathi Ramakrishnan, Elena Lasorsa, Gizzou Azabdaftari, Alejandro Godoy, Roberto Pili

Research output: Contribution to journalArticle

Abstract

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-γH2AX. 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.

Original languageEnglish (US)
Pages (from-to)2225-2236
Number of pages12
JournalOncotarget
Volume4
Issue number12
StatePublished - Dec 2013
Externally publishedYes

Fingerprint

Histone Deacetylases
Androgen Receptors
Phosphatidylinositol 3-Kinases
Prostatic Neoplasms
DNA Damage
Apoptosis
Ataxia Telangiectasia Mutated Proteins
Cell Line
Double-Stranded DNA Breaks
Therapeutics
DNA Repair
panobinostat
Neoplasms
Clinical Trials
dactolisib

Keywords

  • ATM
  • BEZ235
  • DNA damage
  • Panobinostat
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology

Cite this

Ellis, L., Ku, S. Y., Ramakrishnan, S., Lasorsa, E., Azabdaftari, G., Godoy, A., & Pili, R. (2013). Combinatorial antitumor effect of HDACs and the PI3K-Akt-mTOR pathway inhibition in a Pten deficient model of prostate cancer. Oncotarget, 4(12), 2225-2236.

Combinatorial antitumor effect of HDACs and the PI3K-Akt-mTOR pathway inhibition in a Pten deficient model of prostate cancer. / Ellis, Leigh; Ku, Sheng Yu; Ramakrishnan, Swathi; Lasorsa, Elena; Azabdaftari, Gizzou; Godoy, Alejandro; Pili, Roberto.

In: Oncotarget, Vol. 4, No. 12, 12.2013, p. 2225-2236.

Research output: Contribution to journalArticle

Ellis, L, Ku, SY, Ramakrishnan, S, Lasorsa, E, Azabdaftari, G, Godoy, A & Pili, R 2013, 'Combinatorial antitumor effect of HDACs and the PI3K-Akt-mTOR pathway inhibition in a Pten deficient model of prostate cancer', Oncotarget, vol. 4, no. 12, pp. 2225-2236.
Ellis L, Ku SY, Ramakrishnan S, Lasorsa E, Azabdaftari G, Godoy A et al. Combinatorial antitumor effect of HDACs and the PI3K-Akt-mTOR pathway inhibition in a Pten deficient model of prostate cancer. Oncotarget. 2013 Dec;4(12):2225-2236.
Ellis, Leigh ; Ku, Sheng Yu ; Ramakrishnan, Swathi ; Lasorsa, Elena ; Azabdaftari, Gizzou ; Godoy, Alejandro ; Pili, Roberto. / Combinatorial antitumor effect of HDACs and the PI3K-Akt-mTOR pathway inhibition in a Pten deficient model of prostate cancer. In: Oncotarget. 2013 ; Vol. 4, No. 12. pp. 2225-2236.
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