4,5-Diphenyl-2-methyl picolinate induces cellular senescence by accumulating DNA damage and activating associated signaling pathways in gastric cancer.
4,5-Diphenyl-2-methyl picolinate induces cellular senescence by accumulating DNA damage and activating associated signaling pathways in gastric cancer.
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4,5-二苯基-2-甲基吡啶甲酸通过累积 DNA 损伤并激活胃癌中的相关信号通路来诱导细胞衰老。
DOI：
10.1016/j.lfs.2019.116973
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发表时间：
2019-12
期刊：
影响因子：
--
通讯作者：
Tu Z
中科院分区：
文献类型：
--
作者：
Zhao Z;Shang D;Qiu L;Guo C;Li Y;Liu H;Yuan G;Tu Z
目的胃癌是一种常见的恶性肿瘤，其生存率较低.细胞衰老是一种有效的抗癌机制，是自然发生的，并且可以由化疗剂诱导。我们试图探索新的化合物对GC细胞通过诱导细胞senescence.Main methodsPrimary筛选的一个库的N-杂环化合物确定了一些有效的抑制作用对GC细胞。此外，通过经典测定法，包括衰老相关（SA）-β-半乳糖苷酶染色和免疫荧光，研究了最有效的候选化合物对GC细胞增殖和衰老的体外作用;并且在异种移植肿瘤小鼠模型中评价该化合物的体内效应。关键发现在43种测试化合物中，4，5-二苯基-2-甲基吡啶甲酸酯（5-diphenyl-2-methyl picolinate，5-diphenyl-2-methyl picolinate，5-diphenyl-2-methyl picolinate，5-diphenyl-2-methyl picolinate，5-diphenyl-2-methyl picolinate）对胃癌细胞生长的抑制作用最强。体外实验表明，甘草酸通过诱导衰老和DNA损伤相关的蛋白标志物和信号通路抑制肿瘤细胞增殖;体内实验证实甘草酸通过促进DNA损伤信号通路抑制肿瘤生长。并揭示了顺铂通过靶向GC癌中的DNA损伤和相关信号通路诱导细胞衰老而发挥抗癌作用。
AimsGastric cancer (GC) is a common cancer with a relatively low survival rate. Cellular senescence, a potent anti-cancer mechanism, is naturally occurred, and can be induced by chemotherapeutic agents. We sought to explore new compounds against GC cells by inducing cellular senescence.Main methodsPrimary screening of a library of N-heterocyclic compounds identified some with potent inhibitory effects on GC cells. Furthermore, in vitro effects of the most potent candidate compound on the proliferation and senescence of GC cells were studied by classical assays, including senescence-associated (SA)-β-galactosidase staining, and immunofluorescence; andin vivoeffects of this compound was evaluated in a xenograft tumor mouse model.Key findingsAmong 43 tested compounds, 4,5-diphenyl-2-methyl picolinate (DMP) showed the highest inhibition effects on the growth of GC cells. In vitro experiments showed that DMP inhibited the proliferation by inducing senescence and DNA-damage associated protein markers and signaling pathways.In vivoexperiment confirmed that DMP treatment inhibited tumor growth by promoting DNA-damage signaling.SignificanceThis study set up a platform to identify senescence-inducing anti-cancer compounds, and uncovers that DMP exerted anticancer effects by inducing cellular senescence through targeting DNA damage and associated signaling pathways in GC cancer.
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