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: 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.

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

“…Such encouraging results may constitute an important breakthrough not only to enrich the quality of life of NSAIDs chronic users, but also to allow the use of these medicines in the therapy of a wider spectrum of diseases. In fact, diverse preclinical studies have been showing the efficacy of phospho‐NSAIDs, NO‐NSAIDs, H 2 S‐NSAIDs, NOSH‐NSAIDs, dual COX/5‐LOX inhibitors, and mPGES‐1 inhibitors as antitumor and/or neuroprotective agents . Therefore, the development of safer anti‐inflammatory drugs may additionally provide valuable options for the long‐term treatment of cancer and neurodegenerative diseases.…”

“…Indeed, some proof‐of‐concept animal studies have already shown that NOSH‐derivatives of aspirin, sulindac, and naproxen (Fig. ) exhibit anti‐inflammatory, analgesic, antipyretic, antiplatelet, and antioxidant activities, while sparing the GI tract . For instance, NOSH‐aspirin has displayed superior antinociceptive activity in different animal models of inflammatory pain, as well as greater GI tolerability and antioxidant properties .…”

The dichotomous role of H2S in cancer cell biology? Déjà vu all over again

“…The structural components of three of these compounds are shown in Fig 4G-I. In terms of GI safety, NBS-1120 [325], AVT-219 [326], and NOSH-sulindac (AVT-18A) [327] were essentially devoid of any GI toxicity. All three compounds exhibited comparable pharmacological properties to their respective parent compound but unlike their native counterparts were GI safe.…”

“…The cell growth inhibitory properties of NBS-1120, NBS-1121, AVT-219, and AVT-18A were evaluated in eleven different human cancer cell lines of six different histological subtypes [325–327]. All four NOSH compounds were extremely effective in inhibiting the growth of these cell lines, however, NBS-1120 was the most potent, with IC 50 s for cell growth inhibition ranging from 48–280 nM at 24h [324, 326, 327].…”

“…All four NOSH compounds were extremely effective in inhibiting the growth of these cell lines, however, NBS-1120 was the most potent, with IC 50 s for cell growth inhibition ranging from 48–280 nM at 24h [324, 326, 327]. …”