Therapeutic value of quinazoline-based compounds in prostate cancer.
Therapeutic value of quinazoline-based compounds in prostate cancer.
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发表时间：
2013-11
影响因子：
2
通讯作者：
J. Bilbro;M. Mart;N. Kyprianou
中科院分区：
文献类型：
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作者：
J. Bilbro;M. Mart;N. Kyprianou
某些α1肾上腺素受体拮抗剂在不影响细胞增殖的情况下诱导显著的细胞凋亡和损伤肿瘤血管，这是喹唑啉结构所特有的效应。这些抗癌作用被归因于通过破坏整合素介导的细胞生存途径来诱导经典的细胞凋亡和逆转失巢耐药。最近的药物优化工作已经产生了几个具有喹唑啉衍生化学结构的新化合物，这些化合物通过失巢蛋白发挥了强大的抗肿瘤活性。临床前和临床研究的结果暗示了基于喹唑啉的类似物在前列腺癌预防和治疗中的潜在价值。对我们中心的一大批患者进行的一项回顾性研究显示，使用α1-雄受体拮抗剂治疗可显著降低前列腺癌的发生风险，这表明这些经FDA批准的药物具有潜在的化学预防机制。在这篇综述中，我们讨论了目前对前列腺癌中喹唑啉类化合物逆转抗失巢蛋白耐药信号机制的理解，以期确定治疗转移性去势耐药前列腺癌(CRPC)的新靶点。
Certain α1-adrenoreceptor antagonists induce significant apoptosis and impair tumor vascularity without affecting cellular proliferation, effects specific to the quinazoline structure. These anticancer effects have been attributed to both induction of classical apoptosis and reversal of anoikis resistance via disruption of integrin-mediated cell survival pathways. Recent drug optimization efforts have generated several novel compounds with quinazoline-derived chemical structure that exert potent anti-tumor activity via anoikis. Results from pre-clinical and clinical studies implicate a potential value of quinazoline-based analogues in prostate cancer prevention and therapy. A retrospective study of a large patient cohort at our center, revealed that treatment with α1-andrenoreceptor antagonists significantly reduced the risk of developing prostate cancer, indicating a potential chemopreventative mechanism for these FDA-approved agents. In the present review we discuss the current understanding of the signaling mechanisms reversing anoikis resistance by the quinazoline-based compounds in prostate tumors, towards enabling identification of novel therapeutic targets for the treatment of metastatic castration-resistant prostate cancer (CRPC).