INDUCTION OF APOPTOSIS BY PROTON PUMP INHIBITOR THROUGH A CASPASE-DEPENDENT PATHWAY IN HUMAN COLON CANCER CELLS
Proton pump inhibitors are the most widely prescribed drugs for the treatment of gastric acid-related diseases, due to their potent ability to suppress gastric acid production. Recent studies suggest that proton pump inhibitors can induce apoptosis in a variety of cancer cells, and an emerging concept for this anti-tumor effect is their ability to change intracellular acidity in these tumor cells. The purpose of this study is to evaluate the effect of a proton pump inhibitor (omeprazole) on apoptosis in a human colon cancer cell line.Main methods: Caco-2 human colorectal cancer cells were incubated with various concentrations of omeprazole in a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and established concentrations resulting in 25% to 50% cell viability were selected for further evaluation. Apoptosis in Caco-2 cells treated with omeprazole at these concentrations was then established using terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling (TUNEL) and 4'-6-diamidino-2-phenylindole (DAPI) staining. Signals related to apoptosis such as caspase-3, caspase-8, Bcl-2, Bax, and PARP expression were then measured using western blot analysis. Key findings: The TUNEL assay showed that omeprazole induced apoptosis in human Caco-2 cells. Expression of the activated forms of major signaling molecules related to apoptosis such as caspase-3, caspase-8 and PARP were significantly increased, and the anti-apoptotic protein Bcl-2 decreased upon treatment with omeprazole. Significant increases in Bax/Bcl-2 expression ratios were also observed in omeprazole-treated cells compared to controls. Significance: These findings demonstrate that application of a proton pump inhibitor induces apoptosis in human colon cancer cells via a caspase-dependent pathway.