Cisplatin (DDP) is the first-line chemotherapeutic agent against lung cancer. However, the therapeutic effect of DDP loses over time due to the acquired drug resistance in non-small cell lung cancer (NSCLC) cells. In recent years, the role of the traditional Chinese medicine (TCM) cordycepin (Cor) in cancer treatment has been attracting attention. However, the effects of Cor on DDP resistance in NSCLC are unclear. In the present study, we aimed to investigate the effects of Cor in combination with DDP on cell proliferation and apoptosis in NSCLC and explore possible underlying mechanisms. The cell proliferation and apoptosis were analyzed in NSCLC parental (A549) and DDP-resistant (A549DDP) cells treated with DDP alone or in combination with Cor both in vitro and in vivo. Different genes and signaling pathways were investigated between DDP-sensitive and DDP-resistant A549 cells by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The perturbations of the MAPK and PI3K-AKT signaling pathways were evaluated by Western blot analysis. Our data showed that Cor markedly enhanced DDP inhibition on cell proliferation and promotion of apoptosis compared to the DDP-alone group in both A549 and A549DDP cells. The synergic actions were associated with activation of AMPK; inhibition of AKT, mTOR, and downstream P709S6K; and S6 phosphorylation in the AKT pathway compared with DDP alone. Collectively, combination of Cor and DDP has a synergistic effect in inhibiting proliferation and promoting apoptosis of NSCLC cells in the presence or absence of DDP resistance. The antitumor activity is associated with activation of AMPK and inhibition of the AKT pathway to enhance DDP inhibition on NSCLC. Our results suggested that Cor in combination with DDP could be an additional therapeutic option for the treatment of DDP-resistant NSCLC.

顺铂（DDP）是抗肺癌的一线化疗药物。但是，由于在非小细胞肺癌（NSCLC）细胞中获得的耐药性，DDP的治疗效果会随着时间的流逝而消失。近年来，传统中药（TCM）虫草素（Cor）在癌症治疗中的作用已引起关注。但是，Cor对NSCLC中DDP耐药性的影响尚不清楚。在本研究中，我们旨在研究Cor联合DDP对NSCLC细胞增殖和凋亡的影响，并探讨可能的潜在机制。在单独或联合使用DDP处理的NSCLC亲本（A549）和耐DDP（A549DDP）细胞中分析了细胞增殖和凋亡体外 和 体内。通过基因本体论（GO）和《京都基因与基因组百科全书》（KEGG）分析，研究了DDP敏感和DDP耐药A549细胞之间的不同基因和信号传导途径。通过蛋白质印迹分析评估MAPK和PI3K-AKT信号通路的扰动。我们的数据显示，在A549和A549DDP细胞中，与单独使用DDP的组相比，Cor显着增强了DDP对细胞增殖的抑制和凋亡的促进。协同作用与AMPK的激活有关。抑制AKT，mTOR和下游P709S6K; 与仅DDP相比，AKT途径中的S6和S6磷酸化。总体上，在存在或不存在DDP抗性的情况下，Cor和DDP的组合在抑制NSCLC细胞的增殖和促进细胞凋亡方面具有协同作用。该抗肿瘤活性与AMPK的激活和AKT途径的抑制有关，以增强DDP对NSCLC的抑制。我们的结果表明，Cor与DDP结合可能是治疗DDP耐药的NSCLC的另一种治疗选择。