Pristimerin synergizes with gemcitabine through abrogating Chk1/53BP1-mediated DNA repair in pancreatic cancer cells
Pristimerin synergizes with gemcitabine through abrogating Chk1/53BP1-mediated DNA repair in pancreatic cancer cells
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Pristimerin 与吉西他滨协同作用，消除胰腺癌细胞中 Chk1/53BP1 介导的 DNA 修复。
DOI：
10.1016/j.fct.2020.111919
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发表时间：
2021-01-01
影响因子：
4.3
通讯作者：
Tao, Li
中科院分区：
文献类型：
--
作者：
Jiang, Zhuangzhuang;Zhao, Yang;Tao, Li
已经表明，检查点激酶抑制剂可以通过破坏复制应力反应（RSR）来增强对吉西他滨的化学敏感性。在本研究中，我们的目的是描述吉西他滨和喹酮甲酸三萜类丙糖蛋白在胰腺癌（PC）细胞中的化学合成致命作用。药物相互作用测定法表明，吉西他滨和丙二酰蛋白酶以亚-IC50浓度的有效协同作用。有趣的是，原始蛋白诱导的检查点激酶1（CHK1）诱导的溶酶体降解降低了G1/S边界处细胞的百分比，并触发了与单独使用吉西他滨治疗相比，触发了明显的双链DNA断裂。此外，吉西他滨激活了CHK1的磷酸化，并诱导了聚（ADP-核糖）聚合物（PAR）的形成以及53BP1的积累，这部分或完全受到Pristimerin的影响。同时，Pristimerin在吉西他滨治疗后增强了伽马H2AX的表达。最后，吉西他滨与原始蛋白酶的组合增加了PC细胞的凋亡潜力。这些结果表明，原始蛋白酶充当RSR的天然抑制剂，并且是一种新型的治疗策略，即在体内PC模型中应进一步详细研究。
It has been shown that checkpoint kinase inhibitors can enhance chemosensitivity to gemcitabine by disrupting the replication stress response (RSR). In the present study, we aimed to describe the chemical synthetic lethal effects of the combination of gemcitabine and quinone-methide triterpenoid pristimerin in pancreatic cancer (PC) cells. The drug interaction assay indicated effective synergy between gemcitabine and pristimerin at sub-IC50 concentrations. Interestingly, pristimerin induced lysosomal degradation of checkpoint kinase 1 (Chk1), decreased the percentage of cells at the G1/S boundary and triggered significant double-stranded DNA breaks compared to gemcitabine treatment alone. Moreover, gemcitabine activated the phosphorylation of Chk1 and induced the formation of poly (ADP-ribose) polymers (PARs) as well as the accumulation of 53BP1, which was either partially or completely impaired by pristimerin. Meanwhile, pristimerin augmented the expression of gamma H2AX upon gemcitabine treatment. Finally, the combination of gemcitabine with pristimerin increased the apoptotic potential of PC cells. These results show that pristimerin acts as a naturally occurring inhibitor of RSR, and a novel therapeutic strategy of combining pristimerin and gemcitabine deserves further detailed investigation in PC models in vivo.