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

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.