Department of Physiology, Pharmacology and Neuroscience Sophie Davis School of Biomedical Education City University of New York School of Medicine New York NY 10031.
Department of Physiology, Pharmacology and Neuroscience Sophie Davis School of Biomedical Education City University of New York School of Medicine New York NY 10031; Avicenna Pharmaceuticals Inc.New York NY 10019.
Pharmacol Res Perspect. 2016 Mar 4;4(2):e00224. doi: 10.1002/prp2.224. eCollection 2016 Apr.
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) E2. 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.
萘普生（NAP）是一种有效的非甾体抗炎药（NSAID），具有良好的心血管特征。然而，其长期使用可能会导致严重的胃肠道和肾脏副作用。NOSH-（一氧化氮和硫化氢）释放萘普生（NOSH-NAP，AVT-219）属于一类新型抗炎剂，旨在克服这些限制。我们比较了 AVT-219 与 NAP 在临床前动物模型中的胃肠道安全性、抗炎、镇痛、解热和抗血小板特性。我们还评估了其在 11 个人类癌症细胞（HCC）系和结肠癌化疗异种移植小鼠模型中的抗癌作用。AVT-219：（1）在抑制培养的 HCC 生长方面比 NAP 强几个数量级；（2）对胃安全，而 NAP 则导致明显的溃疡；（3）显示出与 NAP 相当的强大抗炎、镇痛、解热和抗血小板特性；（4）NAP 导致血浆肿瘤坏死因子-α（TNFα）显著升高，而在 AVT-219 治疗的大鼠中，这种升高明显较低。从机制上讲，AVT-219 是一种强大的抗氧化剂，抑制环氧化酶（COX）-1 和 -2，从而减少前列腺素（PG）E2。在异种移植中，AVT-219 显著降低肿瘤生长和肿瘤质量，没有胃肠道毒性迹象，而 NAP 治疗的小鼠因胃肠道出血而死亡。AVT-219 在抑制 HCC 生长方面表现出相当大的安全性和效力；是一种有效的镇痛药、解热药、抗血小板药和抗炎药；并且在降低异种移植小鼠模型中已建立肿瘤的生长方面比 NAP 更有效。
