NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model
NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model
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DOI：
10.1016/j.bbrc.2012.02.051
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发表时间：
2012-03-16
影响因子：
3.1
通讯作者：
Kashfi, Khosrow
中科院分区：
文献类型：
--
作者：
Chattopadhyay, Mitali;Kodela, Ravinder;Kashfi, Khosrow
非甾体抗炎药（NSAID）是典型的抗癌药物。然而，长期使用它们与不良胃肠道反应有关。认识到内源性气体介质一氧化氮（NO）和硫化氢（H2S）可以增加粘膜防御机制，导致开发了具有增加的安全性特征的NO和H2S释放NSAID。在这里，我们报告了一种新的混合物，NOSH-阿司匹林，这是一个NO和H2S释放剂。NOSH-阿司匹林抑制HT-29结肠癌生长，在24、48和72 h的IC（50）分别为45.5 +/- 2.5、19.7 +/- 3.3和7.7 +/- 2.2 nM。这是第一个基于NSAID的药物，具有如此高的效力。NOSH-阿司匹林抑制细胞增殖，诱导细胞凋亡，并使细胞周期阻滞于G（0）/G（1）期。重建和结构-活性的研究代表了一个相当接近的完整的分子表明，NOSH-阿司匹林是9000倍，更有效的比它的部分对生长抑制的总和。NOSH-阿司匹林对绵羊考克斯-1的抑制作用大于对绵羊考克斯-2的抑制作用。NOSH-ASA治疗携带人结肠癌异种移植物的小鼠导致体积减少85%。总之，这些结果表明，NOSH-阿司匹林具有很强的抗癌潜力，值得进一步评估。(C)2012 Elsevier Inc. All rights reserved.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are prototypical anti-cancer agents. However, their long-term use is associated with adverse gastrointestinal effects. Recognition that endogenous gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H2S) can increase mucosa] defense mechanisms has led to the development of NO- and H2S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH-aspirin, which is an NO- and H2S-releasing agent. NOSH-aspirin inhibited HT-29 colon cancer growth with IC(50)s of 45.5 +/- 2.5, 19.7 +/- 3.3, and 7.7 +/- 2.2 nM at 24, 48, and 72 h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH-aspirin inhibited cell proliferation, induced apoptosis, and caused G(0)/G(1) cell cycle block. Reconstitution and structure-activity studies representing a fairly close approximation to the intact molecule showed that NOSH-aspirin was 9000-fold more potent than the sum of its parts towards growth inhibition. NOSH-aspirin inhibited ovine COX-1 more than ovine COX-2. NOSH-ASA treatment of mice bearing a human colon cancer xenograft caused a reduction in volume of 85%. Taken together, these results demonstrate that NOSH-aspirin has strong anti-cancer potential and merits further evaluation. (C) 2012 Elsevier Inc. All rights reserved.