Nelfinavir Inhibits the Growth of Small-cell Lung Cancer Cells and Patient-derived Xenograft Tumors
Nelfinavir Inhibits the Growth of Small-cell Lung Cancer Cells and Patient-derived Xenograft Tumors
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DOI：
10.21873/anticanres.14754
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发表时间：
2021-01-01
影响因子：
2
通讯作者：
Dennis, Phillip A.
中科院分区：
文献类型：
--
作者：
Kawabata, Shigeru;Connis, Nick;Dennis, Phillip A.
背景/目的：小细胞肺癌（SCLC）具有侵袭性，预后差。虽然SCLC对化疗的反应比其他类型的肺癌更好，但由于其经常复发，因此很难治愈。需要确定新的药物和分子靶点。材料与方法：我们研究了奈非那韦（一种HIV蛋白酶抑制剂）对SCLC细胞的影响，并使用SCLC患者来源的异种移植（PDX）小鼠模型进行了临床前治疗研究。结果如下：奈非那韦在体外抑制SCLC细胞增殖并诱导细胞死亡，这是通过诱导未折叠蛋白反应（UPR）、抑制雷帕霉素的人工/机械靶点（mTOR）激活以及减少SCLC相关分子（如无丝细胞-鳞状细胞同源物1（ASCL 1））的表达引起的。在体内，奈非那韦抑制SCLC PDX肿瘤的生长，这与诱导UPR和降低ASCL 1表达相关。结论：奈非那韦在体外和体内对小细胞肺癌非常有效，这表明可能将奈非那韦纳入小细胞肺癌患者的临床试验。
Background/Aim: Small-cell lung cancer (SCLC) is aggressive and confers poor prognosis. Although SCLC shows more response to chemotherapy than other types of lung cancer, it is difficult to cure because of its frequent recurrence. New drugs and molecular targets need to be identified. Materials and Methods: We investigated the effect of nelfinavir, an HIV protease inhibitor, on SCLC cells and in preclinical treatment studies using SCLC patient-derived xenograft (PDX) mouse models. Results: Nelfinavir inhibited SCLC cell proliferation and induced cell death in vitro, which was caused by induction of the unfolded protein response (UPR), inhibition of manunalian/mechanistic target of rapamycin (mTOR) activation, and reduction in the expression of SCLC-related molecules such as achaete-scute homolog 1 (ASCL1). In vivo, nelfinavir inhibited the growth of SCLC PDX tumors, which correlated with the induction of UPR and reduced expression of ASCL1. Conclusion: Nelfinavir is highly effective in SCLC in vitro and in vivo, suggesting possible incorporation of nelfinavir into clinical trials for patients with SCLC.