Combined antitumor effect of γ-secretase inhibitor and ABT-737 in Notch-expressing non-small cell lung cancer
Combined antitumor effect of γ-secretase inhibitor and ABT-737 in Notch-expressing non-small cell lung cancer
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DOI：
10.1007/s10147-016-1060-3
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发表时间：
2017-04-01
影响因子：
3.3
通讯作者：
Nishimura, Masaharu
中科院分区：
文献类型：
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作者：
Sakakibara-Konishi, Jun;Ikezawa, Yasuyuki;Nishimura, Masaharu
通过γ-分泌酶抑制剂（GSI）抑制Notch已显示在表达Notch的非小细胞肺癌（NSCLC）中具有抗肿瘤作用，并通过调节Bcl-2家族蛋白诱导细胞凋亡。特别是，Bim，Bcl-2蛋白家族的仅BH 3成员，在用GSI处理细胞时在NSCLC中诱导细胞凋亡中具有重要作用。ABT-737是一种仅含BH 3的模拟物，靶向促存活Bcl-2家族，也诱导凋亡。采用MTT增殖试验和异种移植小鼠模型评价GSI和ABT-737的联合抗肿瘤作用。Western blotting分析单药或联合用药对细胞Notch通路和Bcl-2家族表达的影响，结果表明GSI XX或ABT-737单独用药呈剂量依赖性抑制细胞增殖，联合用药具有协同抗肿瘤作用。在体内，与单一药物治疗相比，该药物组合显著抑制肿瘤增殖。磷酸化Bcl-2被下调，Bax被上调的单一和组合药物治疗。Bim由单一药物处理诱导，并通过联合处理增强。联合治疗诱导的细胞凋亡减少Bim抑制，这表明药物组合的抗肿瘤作用依赖于Bim。根据我们的数据，我们建议，联合治疗是一个有前途的策略，为NSCLC的治疗。
Inhibition of Notch by gamma-secretase inhibitor (GSI) has been shown to have an antitumor effect in Notch-expressing non-small cell lung cancer (NSCLC) and to induce apoptosis through modulation of Bcl-2 family proteins. In particular, Bim, a BH3-only member of the Bcl-2 family of proteins, has an important role in the induction of apoptosis in NSCLC when cells are treated with GSI. ABT-737, a BH3-only mimetic, targets the pro-survival Bcl-2 family and also induces apoptosis.The Notch-expressing NSCLC cell lines H460, A549, H1793, and HCC2429 were used. The combined antitumor effect of GSI and ABT-737 was evaluated using the MTT proliferation assay in vitro and in xenograft mouse models. The expression of the Notch pathway and Bcl-2 family was analyzed using Western blotting analysis when cells were treated with a single drug treatment or a combination treatment.GSI XX or ABT-737 alone inhibited cell proliferation in a dose-dependent manner, and combination drug treatment showed a synergistic antitumor effect in vitro. In vivo, this drug combination significantly suppressed tumor proliferation compared to the single drug treatment. Phospho-Bcl-2 was downregulated and Bax was upregulated by both the single and combination drug treatments. Bim was induced by a single drug treatment and was enhanced by combination treatment. Combination treatment-induced apoptosis was decreased by Bim inhibition, suggesting that the antitumor effect of the drug combination was dependent on Bim.Based on our data, we propose that the combination treatment is a promising strategy for NSCLC therapy.