Gemcitabine and APG-1252, a novel small molecule inhibitor of BCL-2/BCL-XL, display a synergistic antitumor effect in nasopharyngeal carcinoma through the JAK-2/STAT3/MCL-1 signaling pathway.
Gemcitabine and APG-1252, a novel small molecule inhibitor of BCL-2/BCL-XL, display a synergistic antitumor effect in nasopharyngeal carcinoma through the JAK-2/STAT3/MCL-1 signaling pathway.
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吉西他滨和新型 BCL-2/BCL-XL 小分子抑制剂 APG-1252 通过 JAK-2/STAT3/MCL-1 信号通路在鼻咽癌中发挥协同抗肿瘤作用
DOI：
10.1038/s41419-021-04042-7
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发表时间：
2021-08-05
影响因子：
9
通讯作者：
Yang DJ
中科院分区：
文献类型：
--
作者：
Luo F;Lu FT;Qiu MZ;Zhou T;Ma WJ;Luo M;Zeng KM;Luo QY;Pan WT;Zhang L;Xia ZF;Zhang ZH;Cao JX;Zhao HY;Zhang L;Yang DJ
晚期鼻咽癌预后差，姑息性化疗效果不佳。不幸的是，几乎没有有效的治疗方案。因此，我们需要具有增强功效的新型治疗策略。本研究旨在研究BCL-2/BCL-XL双重抑制剂APG-1252-M1单药及与吉西他滨联合用药的抗肿瘤疗效。我们应用各种凋亡测定和皮下移植的NPC模型来评估体外和体内抗肿瘤活性。此外，利用磷酸酪氨酸激酶芯片研究了联合治疗的潜在协同机制。此外，使用免疫组织化学和蛋白质印迹进行进一步验证。在体外实验中，我们观察到APG-1252-M1对NPC细胞具有中等的抗肿瘤活性，但它显著提高了吉西他滨促进NPC细胞凋亡和抑制侵袭、迁移和增殖的能力。其中，APG-1252与吉西他滨联合使用时，体内抗肿瘤活性更显著。在机制上，药物组合通过激活半胱天冬酶依赖性途径、阻断磷酸化（p）-JAK-2/STAT 3/MCL-1信号传导途径和抑制上皮-间充质转化来协同抑制NPC。综上所述，本研究结果表明APG-1252与吉西他滨联合用药对鼻咽癌具有协同抗肿瘤活性，为鼻咽癌患者提供了一种有前景的治疗模式。
Advanced nasopharyngeal carcinoma (NPC) has a poor prognosis, with an unfavorable response to palliative chemotherapy. Unfortunately, there are few effective therapeutic regimens. Therefore, we require novel treatment strategies with enhanced efficacy. The present study aimed to investigate the antitumor efficacy of APG-1252-M1, a dual inhibitor of BCL-2/BCL-XL, as a single agent and combined with gemcitabine. We applied various apoptotic assays and used subcutaneous transplanted NPC model to assess the in vitro and in vivo antitumor activity. Moreover, phospho-tyrosine kinase array was used to investigate the combined therapy’s potential synergistic mechanism. In addition, further validation was performed using immunohistochemistry and western blotting. In vitro, we observed that APG-1252-M1 had moderate antitumor activity toward NPC cells; however, it markedly improved gemcitabine’s ability to promote NPC cell apoptosis and suppress invasion, migration, and proliferation. Specifically, APG-1252 plus gemcitabine exhibited even remarkable antitumor activity in vivo. Mechanistically, the drug combination synergistically suppressed NPC by activating caspase-dependent pathways, blocking the phospho (p)-JAK-2/STAT3/MCL-1 signaling pathway, and inhibiting epithelial-mesenchymal transition. In conclusion, the results indicated that the combination of APG-1252 and gemcitabine has synergistic anticancer activities against NPC, providing a promising treatment modality for patients with NPC.
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影响因子：
8.8
作者：
Hellemans, P;van Dam, P A;Weyler, J;van Oosterom, A T;Buytaert, P;Van Marck, E
通讯作者：
Van Marck, E
影响因子：
168.9
作者：
Campbell, PJ;Scott, LM;Green, AR
通讯作者：
Green, AR
细胞外基质重塑激活跨膜受体酪氨酸激酶 DDR1-STAT3 级联促进葡萄膜黑色素瘤肝转移定植
影响因子：
39.3
作者：
Dai W;Liu S;Wang S;Zhao L;Yang X;Zhou J;Wang Y;Zhang J;Zhang P;Ding K;Li Y;Pan J
通讯作者：
Pan J
影响因子：
50.5
作者：
Foo, KF;Tan, EH;Machin, D
通讯作者：
Machin, D
影响因子：
2.3
作者：
Jarnicki A;Putoczki T;Ernst M
通讯作者：
Ernst M