NSC606985, a novel camptothecin analog, induces apoptosis and growth arrest in prostate tumor cells
NSC606985, a novel camptothecin analog, induces apoptosis and growth arrest in prostate tumor cells
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DOI：
10.1007/s00280-008-0740-8
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发表时间：
2009-01-01
影响因子：
3
通讯作者：
Zhu, Yuan-Shan
中科院分区：
文献类型：
--
作者：
Tan, Chen;Cai, Li-Qun;Zhu, Yuan-Shan
目的前列腺癌是美国男性癌症死亡的主要原因。一旦前列腺癌已经转移，目前没有可用的治愈性治疗。因此，开发有效的药物是防治这种疾病的持续努力。本研究以前列腺癌DU-145、LNCaP和PC-3细胞为研究对象，探讨水溶性喜树碱类似物NSC 606985（NSC）对前列腺癌细胞的作用及其可能机制。检测细胞增殖、细胞周期、细胞凋亡和caspase 3/7活性。Bax和巴克的水平，并从线粒体释放细胞色素c进行了分析，通过Western blot.Results治疗与NSC在纳摩尔浓度产生的时间和剂量依赖性的减少多个前列腺癌细胞的活细胞数。在DU-145细胞中，NSC产生时间和剂量依赖性的细胞凋亡和细胞周期阻滞诱导，如细胞形态学变化，S期和亚G1期细胞分数增加，caspase 3/7活性升高，DNA片段化和凋亡细胞。NSC可增加DU-145细胞凋亡蛋白Bax和巴克的水平，并诱导细胞色素c从线粒体释放到胞浆中。Z-VAD-FMK（一种泛半胱天冬酶抑制剂）联合给药可阻断NSC诱导的半胱天冬酶3/7活性和细胞凋亡，而不影响NSC诱导的细胞周期阻滞。与此相反，共同管理的PKC δ抑制剂，rottlerin，没有显着影响NSC诱导的半胱天冬酶活性，并轻微增强神经干细胞诱导的细胞死亡。结论NSC能抑制前列腺肿瘤细胞的生长，诱导细胞凋亡，并导致细胞生长停滞，其机制可能与拓扑异构酶1的相互作用及线粒体凋亡途径的激活有关。
Purpose Prostate cancer is a major cause of cancer mortality in American males. Once prostate cancer has metastasized, there is currently no curative therapy available. The development of effective agents is therefore a continuing effort to combat this disease. In the present study, the effects and potential mechanisms of NSC606985 (NSC), a water-soluble camptothecin analog, in prostate cancer cells were investigated.Methods Prostatic tumor cells, DU-145, LNCaP and PC-3, were used for the study. Cell proliferation, cell cycle, cell apoptosis and caspase 3/7 activity were determined in the presence or absence of NSC. The levels of Bax and Bak, and the release of cytochrome c from mitochondria were analyzed by Western blot.Results Treatment with NSC at nanomolar concentrations produced a time- and dose-dependent decrease in viable cell numbers of multiple prostate cancer cells. In DU-145 cells, NSC produced a time- and dose-dependent induction of cell apoptosis and cell cycle arrest as evidenced by cell morphological changes, increases in S-phase and sub-G1 cell fractions, an elevation of caspase 3/7 activity, DNA fragmentation and apoptotic cells. NSC increased the levels of apoptotic proteins, Bax and Bak, and induced a release of cytochrome c from mitochondria to cytosol in DU-145 cells. Co-administration of Z-VAD-FMK, a pan-caspase inhibitor, blocked NSC-induced caspase 3/7 activity and cell apoptosis without affecting NSC-induced cell cycle arrest. In contrast, co-administration of a PKC delta inhibitor, rottlerin, had no significant effect on NSC induction of caspase activity, and slightly potentiated NSC-induced cell death. Furthermore, like camptothecin, a mutation of topoisomerase 1 that prevents the binding of camptothecin to the enzyme completely abolished the NSC effect in DU-145 cells.Conclusion The data obtained suggest that NSC is able to decrease cell growth, induce cell apoptosis and cause growth arrest in prostatic tumor cells, which may involve an interaction with topoisomerase 1 and an activation of mitochondrial apoptotic pathway.