Lobaplatin-Induced Apoptosis Requires p53-Mediated p38MAPK Activation Through ROS Generation in Non-Small-Cell Lung Cancer
Lobaplatin-Induced Apoptosis Requires p53-Mediated p38MAPK Activation Through ROS Generation in Non-Small-Cell Lung Cancer
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DOI：
10.3389/fonc.2019.00538
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发表时间：
2019-07-24
影响因子：
4.7
通讯作者：
Chen, Jibei
中科院分区：
文献类型：
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作者：
Zhang, Hongming;Chen, Runzhe;Chen, Jibei
以铂类为基础的化疗被推荐为晚期非小细胞肺癌（NSCLC）患者的一线治疗方案。洛铂（LBP）是第三代铂类抗肿瘤药物，已显示出改善的疗效。本研究旨在探讨枸杞多糖诱导野生型A549 p53细胞凋亡的机制。采用CCK-8法、流式细胞术、Western blot法、肿瘤移植模型、TUNEL法和RNA干扰等方法进行研究。结果表明LBP对A549细胞的增殖有明显的抑制作用。在较低浓度下，LBP触发A549细胞的细胞周期停滞在G1期。LBP还可诱导A549细胞凋亡。LBP还增加PARP和Bax的表达以及caspase-3、caspase-8和caspase-9的切割，并降低Bcl-2的表达。体内实验证实LBP能抑制A549移植瘤的生长，并诱导细胞凋亡。转染p53 shRNA或用活性氧抑制剂NAC和p38 MAPK抑制剂SB 203580处理后，A549细胞凋亡减少，提示p53/ROS/p38 MAPK途径可能介导了LBP诱导的A549细胞凋亡。我们的数据表明，LBP可能是一个有前途的候选人治疗非小细胞肺癌与野生型p53。
Platinum-based chemotherapy is recommended as the first-line treatment regimen for patients with advanced non-small-cell lung cancer (NSCLC). Lobaplatin (LBP), a third-generation platinum anti-neoplastic agent, has shown an improved efficacy. This study is aimed to investigate the mechanisms of LBP-induced apoptosis in the A549 p53 wild-type cell line. The Cell Counting Kit-8 assay (CCK-8), flow cytometry (FCM), Western blot, xenograft tumor models, terminal deoxynucleotide transferase dUTP nick end labeling (TUNEL), and RNA interference were used in this study. Our results showed that the proliferation of A549 cells could be inhibited by LBP. At lower concentrations, LBP triggered cell cycle arrest at the G1 phase in A549 cells. LBP could also induce apoptosis of A549 cells. LBP also increased the expression of PARP and Bax and the cleavage of caspase-3, caspase-8, and caspase-9 and reduced Bcl-2 expression. In vivo experiment confirmed that LBP could inhibit tumor growth in the A549 xenograft models and induce apoptosis. Apoptosis of A549 cells was decreased after transfected with p53 shRNA or treated with reactive oxygen species inhibitor NAC and p38MAPK inhibitor SB203580, suggesting that the p53/ROS/p38MAPK pathway appeared to mediate the LBP-induced apoptosis of A549 cells. Our data demonstrate that LBP could be a promising candidate for the treatment of NSCLC with wild-type p53.