Esomeprazole overcomes paclitaxel‐resistance and enhances anticancer effects of paclitaxel by inducing autophagy in A549/Taxol cells

Abstract

Non‐small‐cell lung cancer (NSCLC) is one of the most common malignancies, and the occurrence of drug‐resistance severely limits the efficacy of anticancer drugs in the treatment of NSCLC. Identification of new agents to reverse drug‐resistance in NSCLC treatment is of great importance and urgency both clinically and scientifically. In the present study, we found that A549/Taxol cells displayed a high level of resistance to paclitaxel with the resistance index up to 231. Importantly, esomeprazole could potentiate the antiproliferative effect of paclitaxel in A549/Taxol cells, but not in A549 cells. Further exploration on the underlying mechanisms revealed that esomeprazole decreased the intracellular pH via inhibiting V‐ATPase expression in A549/Taxol cells. Meanwhile, esomeprazole pretreatment significantly promoted paclitaxel‐induced polymerization of tubulin and enhanced the proportion of G2/M‐arrested cells in A549/Taxol cells. Unfortunately, esomeprazole could only result in a slight decrease in the expression of P‐gp in A549/Taxol cells. Interestingly, esomeprazole significantly increased paclitaxel‐induced apoptosis, which was impeded by the autophagy inhibitor 3‐MA in A549/Taxol cells. Taken together, our data suggest that esomeprazole is a promising chemosensitizer against paclitaxel‐resistant NSCLC by inducing autophagy. Our study also offers a new strategy to solve the paclitaxel‐resistance problem during NSCLC treatment.

A Compressive Review about Taxol®: History and Future Challenges

“…Today, there is a great controversy about the role of autophagy in the death and survival of tumor cells. Although some research assures that autophagy is one of the mechanisms of antitumor agents, such as Taxol ® , for killing cancer cells, others suggest that it is a cell survival mechanism [ 124 , 125 , 126 , 127 ]. Therefore, it is necessary to continue conducting research to clarify how autophagy influences the development of cancer and to develop new therapeutic treatments [ 128 ].…”

Oxidative stress‐mediated up‐regulation of ABC transporters in lung cancer cells

“…The fact that only the gene expressions of PGP were induced might be due to the fact that PGP was the most predominant transporter coping with xenobiotics in A549 cells. [ 40 ] The activities of MRPs detected in this experiment could be partially caused by PGP, due to their overlapping substrate/inhibitor specificities. [ 41,42 ] These results also explained the more effective effects of VAL in enhancing the cellular toxicity of each chemical (Figure 3).…”

Targeting Autophagy with Natural Compounds in Cancer: A Renewed Perspective from Molecular Mechanisms to Targeted Therapy

“…In addition, multidrug resistance is a great challenge for paclitaxel to exert effect on cancers (Wang et al, 2018a). While, it was found that esomeprazole could overcome drug resistance of paclitaxel and enhance its anticancer effects by inducing autophagy in A549/Taxol cells (Bai et al, 2021). In a randomized phase II preoperative study, combination of autophagy inhibitor hydroxychloroquine and gemcitabine and nab-paclitaxel could exert autophagy inhibition in pancreatic cancer patients (Zeh et al, 2020) (Figure 2A).…”