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

Abstract

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 mucosal 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 IC50s of 45.5±2.5, 19.7±3.3, and 7.7±2.2nM at 24, 48, and 72h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH–aspirin inhibited cell proliferation, induced apoptosis, and caused G0/G1 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.