TY - JOUR T1 - The Nitrated Form of Nateglinide Induces Apoptosis in Human Pancreatic Cancer Cells Through a Caspase-dependent Mechanism JF - Anticancer Research JO - Anticancer Res SP - 1333 LP - 1338 DO - 10.21873/anticanres.15601 VL - 42 IS - 3 AU - KOJI NISHI AU - SHUHEI IMOTO AU - TAKURO BEPPU AU - SHOTARO UCHIBORI AU - AYANA YANO AU - YU ISHIMA AU - TOKUNORI IKEDA AU - KENJI TSUKIGAWA AU - MASAKI OTAGIRI AU - KEISHI YAMASAKI Y1 - 2022/03/01 UR - http://ar.iiarjournals.org/content/42/3/1333.abstract N2 - Background/Aim: Nitric oxide (NO) has antitumor activity against various solid tumor cell types in addition to its vasodilatory effect. In the current study, we investigated the effect and mechanism of the synthetic nitrated form (NO2-NAT) of nateglinide, a hypoglycemic agent, on the induction of cell death in human pancreatic cancer cells. Materials and Methods: NO production was evaluated by measuring nitrite (NO2) and nitrate (NO3) (NOx). Apoptotic cell numbers were determined using annexin V. Results: NO2-NAT released nitrate and nitrite ions immediately upon dissolving in aqueous solution. NO2-NAT caused significant extracellular leakage of lactate dehydrogenase (LDH) in the human pancreatic cancer cell lines AsPC1 and BxPC3, and increased annexin-positive cells in a time- and concentration-dependent manner. NO2-NAT also significantly increased the activity of caspases 3 and 7. Exposure to Z-VAD-FMK, a caspase inhibitor, significantly suppressed NO2-NAT-induced cell death. Conclusion: These results indicated that NO2-NAT induces apoptosis in human pancreatic cancer cells and may serve as a new NO-based chemotherapeutic agent for the treatment of pancreatic cancer. ER -