Natural IAP inhibitor Embelin enhances therapeutic efficacy of ionizing radiation in prostate cancer

Abstract

Embelin is an active ingredient of traditional herbal medicine that exhibits anti-tumor effects in human prostate cancer cells. However, therapeutic effect of embelin in combination with conventional radiation therapy is not yet determined. In this study, we evaluate the sensitizing potential of embelin on ionizing radiation (IR) in a human prostate cancer model. In vitro, embelin combined with radiation potently suppressed prostate cancer PC-3 cell proliferation that was associated with S and G2/M arrest in cell cycle. Moreover, the combination treatment promoted caspase-independent apoptosis, as evidenced by the increased apoptotic cell death without caspase-3 activation, but not autophagy. Clonogenic survival assay showed that S-phase arrest was required for embelin-mediated radiosensitization. In vivo, embelin significantly improved tumor response to X-ray radiation in the PC-3 xenograft model. Combination therapy produced enhanced tumor growth delay and prolonged time to progression, with minimal systemic toxicity. Immunohistochemistry studies showed that embelin plus IR significantly inhibited cell proliferation, induced apoptosis, and decreased microvessel density in tumors as compared with either treatment alone, suggesting an enhanced combinatory inhibition on tumor suppression and angiogenesis. Our results demonstrate that embelin significantly facilitates tumor suppression by radiation therapy both in vitro and in vivo in the prostate cancer model. This finding warrants embelin as a novel adjuvant therapeutic candidate for the treatment of hormone-refractory prostate cancer that is resistant to radiation therapy.