Combinatorial targeting of the AR for treatment of prostate cancer.

Combining different clinical agents to target multiple pathways in prostate cancer cells, including androgen receptor (AR) signaling, is potentially an effective strategy to improve outcomes for men with metastatic disease. We have previously demonstrated that sub-effective concentrations of an AR antagonist, bicalutamide, a histone deacetylase inhibitor, vorinostat (SAHA), and a hsp90 inhibitor, 17-AAG, act synergistically when combined to cause death of AR-dependent prostate cancer cells. In this study, expression profiling of human prostate cancer cells treated with bicalutamide, vorinostat (SAHA) or 17-AAG, alone or in paired combination, was employed to determine the molecular mechanisms underlying these synergistic interactions. We used microarray analysis to determine the global molecular profile contributing to the synergistic cell death in LNCaP human prostate cancer cells caused by combinations of bicalutamide, vorinostat (SAHA), or 17-AAG. LNCaP human prostate cancer cells were treated for 6 hours with drug treatments as follows: vehicle control, 5 uM bicalutamide, 1 uM vorinostat (SAHA), 40 nM 17-AAG, 5 uM bicalutamide + 40 nM 17-AAG, 40 nM 17-AAG + 1 uM vorinostat (SAHA), or 5 uM bicalutamide + 1 uM vorinostat (SAHA). Each treatment was performed in sextuplicate.