NOSH-sulindac (AVT-18A) is a novel nitric oxide- and hydrogen sulfide-releasing hybrid that is gastrointestinal safe and has potent anti-inflammatory, analgesic, antipyretic, anti-platelet, and anti-cancer properties.

Abstract

Sulindac is chemopreventive and has utility in patients with familial adenomatous polyposis; however, side effects preclude its long-term use. NOSH-sulindac (AVT-18A) releases nitric oxide and hydrogen sulfide, was designed to be a safer alternative. Here we compare the gastrointestinal safety, anti-inflammatory, analgesic, anti-pyretic, anti-platelet, and anti-cancer properties of sulindac and NOSH-sulindac administered orally to rats at equimolar doses. Gastrointestinal safety: 6h post-administration, number/size of hemorrhagic lesions in stomachs were counted. Tissue samples were frozen for PGE2, SOD, and MDA determination. Anti-inflammatory: 1h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 5h. Anti-pyretic: fever was induced by LPS (ip) an hour before administration of the test drugs, core body temperature was measured hourly for 5h. Analgesic: time-dependent analgesic effects were evaluated by carrageenan-induced hyperalgesia. Antiplatelet: anti-aggregatory effects were studied on collagen-induced platelet aggregation of human platelet-rich plasma. Anti-cancer: We examined the effects of NOSH-sulindac on the growth properties of 12 human cancer cell lines of six different tissue origins. Both agents reduced PGE2 levels in stomach tissue; however, NOSH-sulindac did not cause any stomach ulcers, whereas sulindac caused significant bleeding. Lipid peroxidation induced by sulindac was higher than that from NOSH-sulindac. SOD activity was significantly lowered by sulindac but increased by NOSH-sulindac. Both agents showed similar anti-inflammatory, analgesic, anti-pyretic, and anti-platelet activities. Sulindac increased plasma TNFα whereas this rise was lower in the NOSH-sulindac-treated animals. NOSH-sulindac inhibited the growth of all cancer cell lines studied, with potencies of 1000- to 9000-fold greater than that of sulindac. NOSH-sulindac inhibited cell proliferation, induced apoptosis, and caused G2/M cell cycle block. These results demonstrate that NOSH-sulindac is gastrointestinal safe, and maintains the anti-inflammatory, analgesic, antipyretic, and antiplatelet properties of its parent compound sulinsac, with anti-growth activity against a wide variety of human cancer cells.

• Authors: Khosrow Kashfi, Mitali Chattopadhyay, Ravinder Kodela
• Journal: Redox biology (Redox Biol) Vol. 6 Pg. 287-296 (Dec 2015) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 26298203 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Analgesics
• Anti-Inflammatory Agents, Non-Steroidal
• Antineoplastic Agents
• Antipyretics
• Nitric Oxide Donors
• Platelet Aggregation Inhibitors
• Sulindac
• Nitric Oxide
• Malondialdehyde
• Superoxide Dismutase
• Dinoprostone
• Hydrogen Sulfide

Topics

• Administration, Oral
• Analgesics (chemistry, pharmacology)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemistry, pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• Antipyretics (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dinoprostone (metabolism)
• Edema (drug therapy, metabolism, pathology)
• Fever (drug therapy, metabolism, pathology)
• Hydrogen Sulfide (chemistry, pharmacology)
• Hyperalgesia (drug therapy, metabolism, pathology)
• Male
• Malondialdehyde (metabolism)
• Nitric Oxide (chemistry, pharmacology)
• Nitric Oxide Donors (chemistry, pharmacology)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (chemistry, pharmacology)
• Rats
• Rats, Wistar
• Sulindac (analogs & derivatives, pharmacology)
• Superoxide Dismutase (metabolism)