Cordycepin Reverses Cisplatin Resistance in Non-small Cell Lung Cancer by Activating AMPK and Inhibiting AKT Signaling Pathway

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.

Selenium Yeast and Fish Oil Combination Diminishes Cancer Stem Cell Traits and Reverses Cisplatin Resistance in A549 Sphere Cells

“…Recent studies supported the notion that AMPK activation enhances the anticancer effects of cisplatin [ 62 , 63 ]. Nevertheless, some studies reported conflicting results on the tumor-promoting effects of AMPK activation [ 64 , 65 ].…”

Alizarin, a nature compound, inhibits the growth of pancreatic cancer cells by abrogating NF-κB activation

“…Recently, an increasing number of researchers have begun to pay attention to nature compounds which have good antitumor capability and almost no obvious side effects 26 . A growing body of studies has shown that both Chinese herbs and their active components can directly inhibit tumors by inhibiting angiogenesis 27 , blocking the tumor cell growth cycle 28 - 30 , or inducing tumor cell apoptosis 31 , 32 and indirectly inhibit tumors by regulating the tumor microenvironment; for example, by increasing the activity of NK cells 33 , downregulating the immunosuppressive activity of myeloid-derived suppressor cells 28 , 34 , and improving the immune response of dendritic cells 35 . Our lab has been committed to revealing the mechanism of the antitumor activity of nature compounds for years 28 , 30 , 31 , 33 .…”

Exogenous proline enhances susceptibility of NSCLC to cisplatin via metabolic reprogramming and PLK1-mediated cell cycle arrest

“…The results confirmed that FOXM1 activity was reduced by depletion of PLK1 and increased upon cisplatin treatment, accompanied by the increase of CCNB1, ultimately resulting in cell cycle arrest in NSCLC cells with PLK1 deficit. Furthermore, the expression levels of AKT increased in the presence of CDDP accompanied by a decrease of phosphorylated AKT level, indicating that the PI3K/AKT signaling pathway was inhibited upon cisplatin treatment, which might be related to CDDP-induced apoptosis and remained to be further explored ( Liao et al, 2020 ). All above results suggested that PLK1 reduced cisplatin sensitivity in NSCLC cells by regulating multiple signaling molecules.…”