Pyrvinium targets autophagy addiction to promote cancer cell death.
Pyrvinium targets autophagy addiction to promote cancer cell death.
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吡维铵针对自噬成瘾促进癌细胞死亡
DOI：
10.1038/cddis.2013.142
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发表时间：
2013-05-02
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
自噬是一种细胞分解代谢过程，长寿命蛋白质和受损细胞器被溶酶体降解。自噬的激活是一种重要的生存机制，可以保护癌细胞免受各种应激（包括抗癌药物）的影响。最近的研究表明，FDA 批准的抗蠕虫药物双羟萘酸吡维铵具有广泛的抗癌活性。在这里，我们证明吡维铵在体外和体内都能抑制自噬。我们进一步证明，自噬的抑制是雷帕霉素的哺乳动物靶标，但依赖于自噬基因的转录抑制。此外，吡维铵与自噬刺激的组合提高了其对癌细胞的毒性，并且用3-MA或siBeclin1预处理细胞可部分保护细胞在葡萄糖饥饿下免受吡维铵诱导的细胞死亡，这表明靶向自噬成瘾参与了吡维铵介导的细胞毒性。最后，体内研究表明，吡维铵与抗癌和自噬刺激剂2-脱氧-D-葡萄糖（2-DG）的联合治疗在抑制肿瘤生长方面比单独使用吡维铵或2-DG更有效。这项研究支持一种基于针对自噬成瘾的新型癌症治疗策略，并表明使用吡维铵作为自噬抑制剂与化疗药物联合使用以提高其治疗效果。
Autophagy is a cellular catabolic process by which long-lived proteins and damaged organelles are degradated by lysosomes. Activation of autophagy is an important survival mechanism that protects cancer cells from various stresses, including anticancer agents. Recent studies indicate that pyrvinium pamoate, an FDA-approved antihelminthic drug, exhibits wide-ranging anticancer activity. Here we demonstrate that pyrvinium inhibits autophagy both in vitro and in vivo. We further demonstrate that the inhibition of autophagy is mammalian target of rapamycin independent but depends on the transcriptional inhibition of autophagy genes. Moreover, the combination of pyrvinium with autophagy stimuli improves its toxicity against cancer cells, and pretreatment of cells with 3-MA or siBeclin1 partially protects cells from pyrvinium-induced cell death under glucose starvation, suggesting that targeted autophagy addiction is involved in pyrvinium-mediated cytotoxicity. Finally, in vivo studies show that the combination therapy of pyrvinium with the anticancer and autophagy stimulus agent, 2-deoxy-D-glucose (2-DG), is significantly more effective in inhibiting tumor growth than pyrvinium or 2-DG alone. This study supports a novel cancer therapeutic strategy based on targeting autophagy addiction and implicates using pyrvinium as an autophagy inhibitor in combination with chemotherapeutic agents to improve their therapeutic efficacy.
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影响因子：
21.3
作者：
通讯作者：
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Beclin1 通过调节 USP10 和 USP13 的去泛素化活性来控制 p53 的水平。
影响因子：
64.5
作者：
Liu J;Xia H;Kim M;Xu L;Li Y;Zhang L;Cai Y;Norberg HV;Zhang T;Furuya T;Jin M;Zhu Z;Wang H;Yu J;Li Y;Hao Y;Choi A;Ke H;Ma D;Yuan J
通讯作者：
Yuan J
影响因子：
4.9
作者：
Downey, Autumn S.;Chong, Curtis R.;Sullivan, David J.
通讯作者：
Sullivan, David J.
影响因子：
3.6
作者：
Toepfer, Nicholas;Childress, Chandra;Yang, Wannian
通讯作者：
Yang, Wannian
影响因子：
8
作者：
Polager, S.;Ofir, M.;Ginsberg, D.
通讯作者：
Ginsberg, D.