Abstract:

The vacuolar (H+)-ATPases that pump H+ from the cytoplasm to extracellular compartments can alter the pH of the tumor microenvironment. Esomeprazole can effectively inhibit vacuolar (H+)-ATPases and may increase the effectiveness of chemotherapeutics. Therefore, we used esomeprazole in combination with cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, and vinorelbine on the A549 nonsmall-cell lung cancer cell line. Cisplatin and carboplatin combinations with esomeprazole exhibited superior cytotoxicity compared to the other selected chemotherapeutics. Low-dose combinations of esomeprazole with either cisplatin or carboplatin resulted in synergistic interaction. We examined cytotoxic activity of these combinations with the xCELLigence real-time cytotoxicity assay and detected that esomeprazole combinations with both 100% test drug concentrations of cisplatin and carboplatin shifted the antiproliferative effects of these agents towards a cytotoxic effect in a dose-dependent manner. Cell death mode was investigated by M30 assay, Annexin-V-FITC fluorescence imaging, and determination of PARP cleavage in western blotting. The cells treated with the cisplatin and esomeprazole combination displayed characteristic features of apoptosis such as elevated M30 levels, Annexin-V staining, and PARP cleavage. In conclusion, these novel combinations resulted in higher sensitivity of tumors to chemotherapeutics, thereby warranting further in vivo experiments for proof of the concept.

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