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

Autor: Mitali Chattopadhyay, Ravinder Kodela, Khosrow Kashfi
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Male
SUL
sulindac
Platelet Aggregation
NSAIDs
Clinical Biochemistry
Administration
Oral
Pharmacology
PGE2
Prostaglandin E2
Biochemistry
SOD
Superoxide dismutase
Lipid peroxidation
chemistry.chemical_compound
0302 clinical medicine
Sulindac
Malondialdehyde
Edema
Hydrogen Sulfide
Prostaglandin E2
NSAIDs
nonsteroidal anti-inflammatory drugs
LPS
Lipopolysaccharide
0303 health sciences
Analgesics
Platelet
Anti-Inflammatory Agents
Non-Steroidal
NOSH
nitric oxide-hydrogen sulfide
3. Good health
Cyclooxygenase
Hyperalgesia
030220 oncology & carcinogenesis
medicine.symptom
medicine.drug
Research Paper
Gastrointestinal
Antipyretics
Fever
medicine.drug_class
Cell Survival
Analgesic
Pain
Antineoplastic Agents
Nitric Oxide
Anti-inflammatory
Dinoprostone
Nitric oxide
H2S
hydrogen sulfide
03 medical and health sciences
Cell Line
Tumor
medicine
Animals
Nitric Oxide Donors
Antipyretic
Rats
Wistar
Ulcer
030304 developmental biology
MDA
malondialdehyde
Inflammation
NO
nitric oxide
business.industry
Anti-cancer
Superoxide Dismutase
Organic Chemistry
digestive system diseases
Rats
chemistry
business
Platelet Aggregation Inhibitors
Zdroj: Redox Biology
ISSN: 2213-2317
Popis: 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: 6 h post-administration, number/size of hemorrhagic lesions in stomachs were counted. Tissue samples were frozen for PGE2, SOD, and MDA determination. Anti-inflammatory: 1 h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 5 h. Anti-pyretic: fever was induced by LPS (ip) an hour before administration of the test drugs, core body temperature was measured hourly for 5 h. 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.
Graphical abstract
Highlights • NOSH-sulindac is a hybrid compound that releases nitric oxide and hydrogen sulfide. • NOSH-sulindac is gastrointestinal safe but inhibits COX-1. • NOSH-sulindac has anti-inflammatory, antipyretic, anti-platelet, and analgesic properties. • NOSH-sulindac inhibited growth of 12 different human cancer cell lines of 6 different tissue origins. • NOSH-sulindac inhibited proliferation, caused G2/M cell cycle arrest, inducing apoptosis.
Databáze: OpenAIRE
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