Combination therapy, which can optimize killing activity to cancers and minimize drug resistance, is a mainstream therapy against hormone-refractory prostate cancers (HRPCs). Rottlerin, a natural polyphenolic component, synergistically increased PC-3 (a HRPC cell line) apoptosis induced by camptothecin (a topoisomerase I inhibitor). Using siRNA technique to knockdown protein kinase C-δ (PKCδ), the data showed that rottlerin-mediated synergistic effect was PKCδ-independent, although rottlerin has been used as a PKCδ inhibitor. Rottlerin potentiated camptothecin-induced DNA fragmentation at S phase and ATM phosphorylation at Ser1981. The effect was correlated to apoptosis (r2 = 0.9). To detect upstream signals, the data showed that camptothecin acted on and stabilized topoisomerase I-DNA complex, leading to the formation of camptothecin-trapped cleavage complexes (TOP1cc). The effect was potentiated by rottlerin. To determine DNA repair capability, the time-related γH2A.X formation was examined after camptothecin removal. Consequently, rottlerin significantly inhibited camptothecin removal-mediated decline of γH2A.X formation at S phase, indicating the impairment of DNA repair activity in the presence of rottlerin. The combinatory treatment of camptothecin and rottlerin induced conformational change and activation of Bax and formation of truncated Bad, suggesting the contribution of mitochondria stress to apoptosis. In summary, the data suggest that rottlerin-mediated camptothecin sensitization is through the augmented stabilization of TOP1cc, leading to an increase of DNA damage stress and, possibly, an impairment of DNA repair capability. Subsequently, mitochondria-involved apoptosis is triggered through Bax activation and truncated Bad formation. The novel discovery may provide an anticancer approach of combinatory use between rottlerin and camptothecin for the treatment of HRPCs.

译文

:组合疗法可优化对癌症的杀伤活性,并最大程度降低耐药性,是抵抗激素难治性前列腺癌(HRPC)的主流疗法。天然多酚成分Rottlerin协同增加喜树碱(拓扑异构酶I抑制剂)诱导的PC-3(HRPC细胞系)凋亡。使用siRNA技术敲除蛋白激酶C-δ(PKCδ),数据显示,尽管已将rottlerin用作PKCδ抑制剂,但rottlerin介导的协同作用不依赖PKCδ。 Rottlerin增强了喜树碱诱导的S期DNA片段化和Ser1981的ATM磷酸化。该作用与细胞凋亡相关(r2 = 0.9)。为了检测上游信号,数据显示喜树碱作用于拓扑异构酶I-DNA复合物并使其稳定,从而导致喜树碱捕获的裂解复合物(TOP1cc)的形成。劳特林增强了该作用。为了确定DNA修复能力,在喜树碱去除后检查时间相关的γH2A.X的形成。因此,鲁特林显着抑制喜树碱去除介导的S期γH2A.X形成的下降,表明存在鲁特林时DNA修复活性受到损害。喜树碱和rottlerin的联合治疗诱导构象变化和Bax的活化以及截短的Bad的形成,表明线粒体应激对细胞凋亡的贡献。总而言之,数据表明,铁蛋白介导的喜树碱敏化作用是通过增强TOP1cc的稳定性来实现的,从而导致DNA损伤应力增加,并可能损害DNA修复能力。随后,通过Bax激活和截短的Bad形成触发线粒体参与的凋亡。这一新发现可能提供一种在rottlerin和喜树碱之间联合使用的抗癌方法,以治疗HRPC。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录