The Nitrated Form of Nateglinide Induces Apoptosis in Human Pancreatic Cancer Cells Through a Caspase-dependent Mechanism.

Abstract

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.

• Authors: Koji Nishi, Shuhei Imoto, Takuro Beppu, Shotaro Uchibori, Ayana Yano, Y U Ishima, Tokunori Ikeda, Kenji Tsukigawa, Masaki Otagiri, Keishi Yamasaki
• Journal: Anticancer research (Anticancer Res) Vol. 42 Issue 3 Pg. 1333-1338 (Mar 2022) ISSN: 1791-7530 [Electronic] Greece
• PMID: 35220224 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• Antineoplastic Agents
• Nitric Oxide Donors
• Nitric Oxide
• Nateglinide
• CASP3 protein, human
• CASP7 protein, human
• Caspase 3
• Caspase 7

Topics

• Antineoplastic Agents (metabolism, pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Line, Tumor
• Enzyme Activation
• Humans
• Nateglinide (analogs & derivatives, metabolism, pharmacology)
• Nitric Oxide (metabolism)
• Nitric Oxide Donors (metabolism, pharmacology)
• Pancreatic Neoplasms (drug therapy, immunology, pathology)
• Signal Transduction