Abstract
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.
Highlights
Lung cancer is the most common cancer and the leading cause of cancer-related death worldwide
We found that treatment with combination of Cor and DDP significantly increased the sensitivity of nonsmall cell lung cancer (NSCLC) cells to DDP (Figures 1C,D)
We demonstrated that Cor and DDP were synergistic at inhibiting cell proliferation and inducing apoptosis of NSCLC in the presence or absence of DDP resistance
Summary
Lung cancer is the most common cancer and the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) is the major (85%) histological subtype of the disease (Siegel et al, 2019). Cisplatin (DDP) is the firstline chemotherapeutic agent for the treatment of NSCLC owing to its effective anticancer activity. DDP reacts with DNA to induce its characteristic biological effects leading to DNA damage or activation of irreversible apoptotic program (Siddik, 2003). The antineoplastic effect of DDP is greatly hampered by drug resistance (Galluzzi et al, 2012). Most advanced NSCLC acquired DDP resistance leading to tumor growth or distant metastasis over time. The increasing content of GSH is a major contributing factor to cisplatin resistance, because GSH can bind to drugs, interact with ROS, and participate in DNA repair processes (Traverso et al, 2013)
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