Molecular radiosensitization of prostate cancer by modulating cell death pathways Free

A120

Radioresistance markedly impairs the efficacy of cancer therapy and involves anti-apoptotic signal transduction pathways that prevent the treatment-induced cell death. Anti-apoptotic proteins such as Bcl-xL, Bcl-2, Mcl-1, and inhibitors of apoptosis proteins (IAP), are overexpressed in prostate cancer and contribute to prostate tumor initiation, progression and resistance to therapy. They are promising molecular targets for modulating therapeutic resistance of prostate cancer. Anti-apoptotic Bcl-2 family of proteins and IAP family of proteins quickly emerge as highly attractive molecular targets for the development of novel anti-cancer therapy to overcome apoptosis-resistance.
 We recently demonstrated that, (-)-gossypol, a natural product from cottonseed and a potent small molecule inhibitor of both Bcl-2 and Bcl-xL, can radiosensitize prostate cancer cells 10- to 20-fold in clonogenic assays. Fluorescence resonance energy transfer (FRET) assay suggests that (-)-gossypol potently blocks the interaction of Bcl-xL with Bax and Bad, in a time- and dose-dependent manner. In a PC-3 xenograft model in nude mice, orally administered (-)-gossypol achieved a much greater efficacy with long-term tumor regression when used in combination with ionizing radiation. Tumors treated with (-)-gossypol plus radiation showed much more increased apoptosis and reduced angiogenesis than either treatment alone. Mechanism studies indicate that Mcl-1 is also involved in the (-)-gossypol-induced prostate cancer cell death.
 We have also tested a series of novel small-molecule IAP-inhibitors. They bind to XIAP BIR3 domain 20-30-times more potent than Smac peptide, potently antagonize XIAP BIR3, and promote activation of Caspase-3 and Caspase-9 in a dose-dependent manner. They potently enhanced apoptosis induction in cancer cells and sensitized cancer cells to TRAIL and radiation. Biotin-labeled compound pull-down assay showed that XIAP, cIAP-1 and cIAP-2 proteins can be pulled down by the IAP-inhibitors. In nude mouse xenograft models, IAP-inhibitors Embelin and SH-130 potently sensitized the DU-145 tumors to X-ray radiation. Bioluminescence imaging confirmed SH-130 plus radiation resulted in complete tumor regression in 6 out of 10 tumors, comparing 2/10 tumors with radiation alone, and 0/10 tumors with SH-130 alone.
 Taken together, our results demonstrate that small-molecule inhibitors of anti-apoptotic proteins Bcl-2/Bcl-xL or IAPs can overcome apoptosis-resistance and sensitize human prostate cancer to radiation therapy. (-)-Gossypol is now in Phase I-II clinical trials in patients with prostate cancer, and represents the world’s first Bcl-2 inhibitor in clinical study. These studies pave the way to develop the most potent small molecule Bcl-2 or IAP inhibitors as a novel adjuvant therapy for radiosensitizing human prostate cancer with high levels of Bcl-2/IAPs. Molecular modulation of anti-apoptotic proteins may improve the outcome of conventional cancer therapy and represents a promising novel molecularly targeted therapy for human prostate cancer.