Combination Therapy of Antiandrogen and XIAP Inhibitor for Treating Advanced Prostate Cancer

Overexpression of the androgen receptor (AR) and anti-apoptotic genes including X-linked inhibitor of apoptosis protein (XIAP) provide tumors with a proliferative advantage. Therefore, our objective was to determine whether novel antiandrogen (CBDIV17) and XIAP inhibitor based combination therapy can treat advanced prostate cancer. CBDIV17 and embelin-6g were synthesized and their effect on cell proliferation, apoptosis, cell cycle and AR and XIAP gene silencing determined. CBDIV17 was more potent than bicalutamide and inhibited proliferation of C4-2 and LNCaP cells, IC50 for CBDIV17 was similar to 12 mu M and similar to 21 mu M in LNCaP and C4-2 cells, respectively, whereas bicalutamide had IC50 of similar to 46 mu M in LNCaP cells and minimal effect in C4-2 cells. CBDIV17 induced apoptosis more effectively compared to bicalutamide and significantly inhibited DNA replication. Combination of CBDIV17 and embelin resulted in supra-additive antiproliferative and apoptotic effects. Embelin downregulated AR expression and decreased androgen-mediated AR phosphorylation at Ser(81). These hydrophobic drugs were solubilized using micelles prepared with polyethylene glycol-b-poly (carbonate-co-lactide) (PEG-b-p(CB-co-LA)) copolymer. Combination therapy inhibited prostate tumor growth more effectively compared to control or monotherapy in vivo. Our results demonstrated that CBDIV17 in combination with embelin can potentially treat advanced prostate cancer.