Gastrointestinal safety, chemotherapeutic potential, and classic pharmacological profile of NOSH‐naproxen (AVT‐219) a dual NO‐ and H(2)S‐releasing hybrid

Naproxen (NAP) is a potent nonsteroidal anti‐inflammatory drug (NSAID) with a favorable cardiovascular profile. However, its long‐term use may lead to serious gastrointestinal and renal side effects. NOSH‐ (nitric oxide and hydrogen sulfide) releasing naproxen (NOSH‐NAP, AVT‐219) belongs to a new class of anti‐inflammatory agents designed to overcome these limitations. We compared the gastrointestinal safety, anti‐inflammatory, analgesic, antipyretic, and antiplatelet properties of AVT‐219 to that of NAP in preclinical animal models. We also evaluated its anticancer effects in 11 human cancer cell (HCC) lines of six different tissue origins and in a chemotherapeutic xenograft mouse model of colon cancer. AVT‐219: (1) was orders of magnitude more potent than NAP in inhibiting the growth of cultured HCC; (2) was safe to the stomach, whereas NAP caused significant ulceration; (3) showed strong anti‐inflammatory, analgesic, antipyretic, and antiplatelet properties comparable to NAP; and (4) NAP caused a significant rise in plasma tumor necrosis factor‐alpha (TNFα), whereas in the AVT‐219‐treated rats this rise was significantly less. Mechanistically, AVT‐219 was a strong antioxidant, inhibited cyclooxygenase (COX)‐1 and ‐2, thus reducing prostaglandin (PG) E(2). In xenografts, AVT‐219 significantly reduced tumor growth and tumor mass with no sign of GI toxicity, whereas NAP‐treated mice died due to GI bleeding. AVT‐219 displayed considerable safety and potency in inhibiting HCC growth; was an effective analgesic, antipyretic, antiplatelet, and anti‐inflammatory; and was significantly more efficacious than NAP in reducing the growth of established tumors in a xenograft mouse model.