Selective induction of apoptosis with proton pump inhibitor in gastric cancer cells.
OBJECTIVE
To survive in an ischemic microenvironment with a lower extracellular pH, ability to up-regulate proton extrusion is critical for cancer cell survival. Gastric H+/K(+)-ATPase exchanges luminal K+ for cytoplasmic H+ and is the enzyme primarily responsible for gastric acidification. On the basis of the fact that blocking the clearance of acidic metabolites are known to induce the cell death, we hypothesized that pantoprazole (PPZ), one of gastric H+/K(+)-ATPase inhibitors used frequently to treat acid-related diseases, could inhibit growth of tumor cells.


METHODS
Genomic DNA fragmentation, terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling assay, and annexin V staining were performed to detect PPZ-induced apoptosis. Mitogen-activated protein kinase activation and heat shock proteins expression were determined by immunoblot with specific antibodies. The antitumor effect of PPZ was evaluated in vivo by a xenograft model of nude mice.


RESULTS
After PPZ treatment, apoptotic cell death was seen selectively in cancer cells and was accompanied with extracellular signal-regulated kinase deactivation. By contrast, normal gastric mucosal cells showed the resistance to PPZ-induced apoptosis through the overexpression of antiapoptotic regulators including HSP70 and HSP27. In a xenograft model of nude mice, administration of PPZ significantly inhibited tumorigenesis and induced large-scale apoptosis of tumor cells.


CONCLUSIONS
PPZ selectively induced in vivo and in vitro apoptotic cell death in gastric cancer, suggesting that proton pump inhibitors could be used for selective anticancer effects.
Yeo
Marie
M
Genomic Research Center for Gastroenterology, Ajou University School of Medicine, Suwon, Korea.
Kim
Dong-Kyu
DK
Kim
Young-Bae
YB
Oh
Tae Young
TY
Lee
Jong-Eun
JE
Cho
Sung Won
SW
Kim
Hugh Chul
HC
Hahm
Ki-Baik
KB
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology*; D001692:Biological Transport / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000201:enzymology; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D007413:Intestinal Mucosa / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors; D017494:Proton Pumps; D051381:Rats; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D013454:Sulfoxides / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D017304:Annexin A5; D000897:Anti-Ulcer Agents; D001562:Benzimidazoles; D006360:Heat-Shock Proteins; D054328:Proton Pump Inhibitors; D017494:Proton Pumps; D013454:Sulfoxides; D000077402:Pantoprazole; D020928:Mitogen-Activated Protein Kinases; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole