Natural IAP inhibitor Embelin enhances therapeutic efficacy of ionizing radiation in prostate cancer.
Natural IAP inhibitor Embelin enhances therapeutic efficacy of ionizing radiation in prostate cancer.
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DOI：
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发表时间：
2011
影响因子：
5.3
通讯作者：
Yao Dai;Jeffrey Desano;Yang Qu;Wenhua Tang;Yang Meng;T. Lawrence;Liang Xu
中科院分区：
文献类型：
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作者：
Yao Dai;Jeffrey Desano;Yang Qu;Wenhua Tang;Yang Meng;T. Lawrence;Liang Xu
Embelin 是传统草药的活性成分，对人类前列腺癌细胞具有抗肿瘤作用。然而，Embelin 与常规放射治疗相结合的治疗效果尚未确定。在这项研究中，我们评估了 Embelin 在人类前列腺癌模型中对电离辐射 (IR) 的敏化潜力。在体外，embelin 与辐射联合有效抑制前列腺癌 PC-3 细胞增殖，这种增殖与细胞周期中的 S 和 G2/M 停滞相关。此外，联合治疗促进了不依赖于 caspase 的细胞凋亡，这一点可以通过在没有 caspase-3 激活的情况下细胞凋亡增加来证明，但自噬则不会。克隆形成存活测定表明，embelin 介导的放射增敏需要 S 期停滞。在体内，embelin 显着改善了 PC-3 异种移植模型中肿瘤对 X 射线辐射的反应。联合治疗可增强肿瘤生长延迟并延长进展时间，同时全身毒性最小。免疫组织化学研究表明，与单独使用任一治疗方法相比，embelin 联合 IR 显着抑制细胞增殖、诱导细胞凋亡并降低肿瘤中的微血管密度，表明对肿瘤抑制和血管生成的组合抑制作用增强。我们的结果表明，在前列腺癌模型中，embelin 显着促进体外和体内放射治疗对肿瘤的抑制。这一发现证明 Embelin 是一种新的辅助治疗候选药物，用于治疗对放射治疗耐药的激素难治性前列腺癌。
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.