Synergistic anticancer effect of cisplatin and Chal-24 combination through IAP and c-FLIPL degradation, Ripoptosome formation and autophagy-mediated apoptosis.
Synergistic anticancer effect of cisplatin and Chal-24 combination through IAP and c-FLIPL degradation, Ripoptosome formation and autophagy-mediated apoptosis.
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顺铂和 Chal-24 组合通过 IAP 和 c-FLIPL 降解、核糖体形成和自噬介导的细胞凋亡发挥协同抗癌作用。
DOI：
10.18632/oncotarget.2746
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发表时间：
2015-01-30
期刊：
影响因子：
--
通讯作者：
Lin Y
中科院分区：
文献类型：
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作者：
Shi S;Wang Q;Xu J;Jang JH;Padilla MT;Nyunoya T;Xing C;Zhang L;Lin Y
耐药性是抗癌化疗的一大障碍。使用作用机制不同的药物联合治疗可能会增加抗癌效果。我们最近确定了新型查尔酮衍生物查尔酮-24(Chal-24)，作为一种潜在的治疗药物，它通过激活自噬介导的坏死性下垂途径杀死癌细胞。在这份报告中，我们调查了CHAL-24是否可以与一线遗传毒性抗癌药物顺铂联合用于癌症治疗。Chal-24与顺铂联合应用可协同诱导肺癌细胞株的细胞毒作用，其作用依赖于Chal-24诱导的自噬作用。顺铂与Chal-24联合应用可显著增强JNK/Bcl2/Beclin1途径的自噬激活作用，但与Chal-24联合应用可显著抑制RIP1、FADD和Caspase8所形成的Ripoposome复合体的降解，从而抑制Ripoposome介导的细胞凋亡。顺铂和Chal-24联合应用可诱导细胞内类IL-1β转换酶抑制蛋白大片段的急剧降解，从而抑制Ripoposome介导的细胞凋亡。这些结果建立了Chal-24联合顺铂增强抗癌活性的新机制：通过Ripoposome的形成增强细胞凋亡信号，通过c-Flipl的降解释放细胞凋亡刹车。总之，我们的工作表明，CHAL-24和顺铂的联合应用可以提高化疗疗效。
Drug resistance is a major hurdle in anticancer chemotherapy. Combined therapy using drugs with distinct mechanisms of function may increase anticancer efficacy. We have recently identified the novel chalcone derivative, chalcone-24 (Chal-24), as a potential therapeutic that kills cancer cells through activation of an autophagy-mediated necroptosis pathway. In this report, we investigated if Chal-24 can be combined with the frontline genotoxic anticancer drug, cisplatin for cancer therapy. The combination of Chal-24 and cisplatin synergistically induced apoptotic cytotoxicity in lung cancer cell lines, which was dependent on Chal-24-induced autophagy. While cisplatin slightly potentiated the JNK/Bcl2/Beclin1 pathway for autophagy activation, its combination with Chal-24 strongly triggered proteasomal degradation of the cellular inhibitor of apoptosis proteins (c-IAPs) and formation of the Ripoptosome complex that contains RIP1, FADD and caspase 8. Furthermore, the cisplatin and Chal-24 combination induced dramatic degradation of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein large (cFLIPL) which suppresses Ripoptosome-mediated apoptosis activation. These results establish a novel mechanism for potentiation of anticancer activity with the combination of Chal-24 and cisplatin: to enhance apoptosis signaling through Ripoptosome formation and to release the apoptosis brake through c-FLIPL degradation. Altogether, our work suggests that the combination of Chal-24 and cisplatin could be employed to improve chemotherapy efficacy.
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