Sanguinarine suppresses prostate tumor growth and inhibits survivin expression.
Sanguinarine suppresses prostate tumor growth and inhibits survivin expression.
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DOI：
10.1177/1947601910368849
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发表时间：
2010-03
期刊：
影响因子：
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通讯作者：
Gao AC
中科院分区：
文献类型：
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作者：
Sun M;Lou W;Chun JY;Cho DS;Nadiminty N;Evans CP;Chen J;Yue J;Zhou Q;Gao AC
前列腺癌是一种常见病，是美国男性癌症相关死亡的第二大原因。目前的治疗方法已被证明在治疗或控制前列腺癌方面是不够的，因此迫切需要寻找治疗这种疾病的药物。Survivin在去势抵抗性前列腺癌的进展和化疗抵抗中起重要作用。前列腺癌细胞中survivin表达的改变与癌症进展、药物/放疗耐药、预后差和患者生存期短有关。在本研究中，作者对Prestwick化学文库进行了基于细胞的快速筛选，该文库由1120种经美国食品和药物管理局批准的化合物组成，这些化合物已知在人体中的安全性和生物利用度，以确定前列腺癌的潜在生存素抑制剂和抗癌药物。血根碱是一种主要从血根植物中提取的苯并苯胺类生物碱，被认为是一种新的生存素抑制剂，可以选择性地杀死前列腺癌细胞，而不是“正常”的前列腺上皮细胞。作者发现血根碱通过泛素-蛋白酶体系统的蛋白降解抑制survivin蛋白的表达。血根碱诱导人前列腺癌细胞凋亡，抑制其生长和体内肿瘤形成。在DU145人前列腺癌细胞异位植入后3天开始给予血根碱，可减少肿瘤的重量和体积。此外，血根碱可致敏紫杉醇介导的生长抑制和细胞凋亡，为克服紫杉醇耐药提供了一种潜在的治疗策略。这些结果表明，血根碱可以单独或与紫杉醇联合用于治疗过表达survivin的前列腺癌。
Prostate cancer is a frequently occurring disease and is the second leading cause of cancer-related deaths of men in the United States. Current treatments have proved inadequate in curing or controlling prostate cancer, and a search for agents for the management of this disease is urgently needed. Survivin plays an important role in both progression of castration-resistant prostate cancer and resistance to chemotherapy. Altered expression of survivin in prostate cancer cells is associated with cancer progression, drug/radiation resistance, poor prognosis, and short patient survival. In the present study, the authors performed a cell-based rapid screen of the Prestwick Chemical Library consisting of 1120 Food and Drug Administration–approved compounds with known safety and bioavailability in humans to identify potential inhibitors of survivin and anticancer agents for prostate cancer. Sanguinarine, a benzophenanthridine alkaloid derived primarily from the bloodroot plant, was identified as a novel inhibitor of survivin that selectively kills prostate cancer cells over “normal” prostate epithelial cells. The authors found that sanguinarine inhibits survivin protein expression through protein degradation via the ubiquitin-proteasome system. Sanguinarine induces apoptosis and inhibits growth of human prostate cancer cells and in vivo tumor formation. Administration of sanguinarine, beginning 3 days after ectopic implantation of DU145 human prostate cancer cells, reduces both tumor weight and volume. In addition, sanguinarine sensitized paclitaxel-mediated growth inhibition and apoptosis, offering a potential therapeutic strategy for overcoming taxol resistance. These results suggest that sanguinarine may be developed as an agent either alone or in combination with taxol for treatment of prostate cancer overexpressing survivin.