Targeted combinatorial therapy of androgen receptor in androgen-independent prostate cancer cells.

29 Background: Gain of function of androgen receptor (AR) and PI3K/Akt/mTOR pathway due to loss of PTEN function are interrelated determinants of AIPC progression and resistance to antiandrogens. We determined that histone deacetylase inhibitors (HDACi), known to regulate AR expression and transcriptional activity, restore sensitivity to bicalutamide (Bic) of AIPC cells and the combination is synergistic. We postulate that adding a dual inhibitor of PI3K/mTOR would potentiate growth inhibition and apoptotic response. Methods: Androgen-independent, PTEN null AI-LNCaP (AI-cells) and wt PTEN RV1-cell lines were treated for 72h with the HDACi Panobinostat (PAN), the dual PI3K/mTOR inhibitor BEZ235 (E) and Bic as single agents or in doublet or triplet combinations. Growth was measured by MTT assay, Akt/mTOR pathway target proteins p-Akt, p-4EBP1 and p-S6K by western blot. Activation of ligand-independent AR downstream targets: CDC20, IDI1, CDK1, UBE2C, PRDM4 by qRT-PCR. Apoptosis by oligonucleosome quantificat...