Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma.
Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma.
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二甲双胍作为抗衰老药物增强CDK4/6抑制剂对头颈鳞状细胞癌的抗癌功效
DOI：
10.1038/s41419-020-03126-0
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发表时间：
2020-10-28
影响因子：
9
通讯作者：
Wu T
中科院分区：
文献类型：
--
作者：
Hu Q;Peng J;Jiang L;Li W;Su Q;Zhang J;Li H;Song M;Cheng B;Xia J;Wu T
CDK4/6抑制剂在多种实体瘤中显示出有前景的抗肿瘤活性；然而，它们在头颈鳞状细胞癌（HNSCC）中的作用需要进一步研究。 CDK4/6抑制剂诱导的衰老相关分泌表型（SASP）对癌症治疗具有双重作用。解决SASP的需要是CDK4/6抑制剂临床应用中的一个严峻挑战。我们研究了二甲双胍是否可以作为一种抑制衰老的药物来调节 SASP 并增强 CDK4/6 抑制剂在 HNSCC 中的抗癌功效。在这项研究中，通过体外测定、HSC6 异种移植模型和患者来源的异种移植模型研究了 CDK4/6 抑制剂 LY2835219 和二甲双胍联合治疗 HNSCC 的疗效。采用衰老相关β-半乳糖苷酶染色、抗体阵列、成球实验和体内肿瘤发生实验检测二甲双胍对LY2835219诱导的衰老和SASP的影响。我们发现LY2835219与二甲双胍联合通过诱导体外和体内细胞周期停滞来协同抑制HNSCC。二甲双胍通过抑制 mTOR 和 stat3 途径显着调节 LY2835219 引发的 SASP 谱。 LY2835219 诱导的 SASP 导致癌症干性上调，而与二甲双胍联合使用可以减弱这种现象。此外，结果表明二甲双胍对干性的抑制与 IL6-stat3 轴的阻断有关。生存分析表明，IL6 和干性标记物的过度表达与 HNSCC 患者的生存率较差相关，这表明以这些蛋白为靶点的二甲双胍可能会改善患者的预后。总的来说，我们的数据表明二甲双胍可以作为一种衰老药物，通过重新编程 SASP 的特性来增强 CDK4/6 抑制剂的抗癌功效。
CDK4/6 inhibitors show promising antitumor activity in a variety of solid tumors; however, their role in head and neck squamous cell carcinoma (HNSCC) requires further investigation. The senescence-associated secretory phenotype (SASP) induced by CDK4/6 inhibitors has dual effects on cancer treatment. The need to address the SASP is a serious challenge in the clinical application of CDK4/6 inhibitors. We investigated whether metformin can act as a senostatic drug to modulate the SASP and enhance the anticancer efficacy of CDK4/6 inhibitors in HNSCC. In this study, the efficacy of a combination of the CDK4/6 inhibitor LY2835219 and metformin in HNSCC was investigated in in vitro assays, an HSC6 xenograft model, and a patient-derived xenograft model. Senescence-associated β-galactosidase staining, antibody array, sphere-forming assay, and in vivo tumorigenesis assay were used to detect the impacts of metformin on the senescence and SASP induced by LY2835219. We found that LY2835219 combined with metformin synergistically inhibited HNSCC by inducing cell cycle arrest in vitro and in vivo. Metformin significantly modulated the profiles of the SASP elicited by LY2835219 by inhibiting the mTOR and stat3 pathways. The LY2835219-induced SASP resulted in upregulation of cancer stemness, while this phenomenon can be attenuated when combined with metformin. Furthermore, results showed that the stemness inhibition by metformin was associated with blockade of the IL6-stat3 axis. Survival analysis demonstrated that overexpression of IL6 and stemness markers was associated with poor survival in HNSCC patients, indicating that including metformin to target these proteins might improve patient prognosis. Collectively, our data suggest that metformin can act as a senostatic drug to enhance the anticancer efficacy of CDK4/6 inhibitors by reprogramming the profiles of the SASP.
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用FDA批准的利托那韦和二甲双胍靶向多发性骨髓瘤的代谢可塑性。
DOI：
10.1158/1078-0432.ccr-14-1088
发表时间：
2015-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
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影响因子：
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作者：
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DOI：
10.1038/nrd.2017.116
发表时间：
2017-10
期刊：
Nature reviews. Drug discovery
影响因子：
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作者：
Childs BG;Gluscevic M;Baker DJ;Laberge RM;Marquess D;Dananberg J;van Deursen JM
通讯作者：
van Deursen JM