PT  - JOURNAL ARTICLE
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
TI  - The Nitrated Form of Nateglinide Induces Apoptosis in Human Pancreatic Cancer Cells Through a Caspase-dependent Mechanism
AID  - 10.21873/anticanres.15601
DP  - 2022 Mar 01
TA  - Anticancer Research
PG  - 1333--1338
VI  - 42
IP  - 3
4099  - http://ar.iiarjournals.org/content/42/3/1333.short
4100  - http://ar.iiarjournals.org/content/42/3/1333.full
SO  - Anticancer Res2022 Mar 01; 42
AB  - 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.