Abstract 3899: NOSH compounds: Nitric oxide- and hydrogen sulfide-releasing hybrids, a new class of anti-inflammatory pharmaceuticals

Abstract

Abstract Introduction: The clinical usefulness of non-steroidal anti-inflammatory drugs (NSAIDs) combined with their potentially life-threatening toxicity has prompted intensive efforts to identify safer alternatives, which will at least maintain their pharmacological properties. The search for a “better NSAID” has resulted in at least two modified hybrids, one that releases nitric oxide (NO-NSAIDs), and another that releases hydrogen sulfide (HS-NSAIDs). These agents although much safer and more potent than their traditional counterparts, have IC50s for cell growth inhibition that are in the micro-molar range. Therefore, we postulated that a new hybrid that incorporated the active parts of each compound may be more potent and effective than either one. Our hypothesis has proved to be correct. We have synthesized a number of NSAID based NOSH (nitric oxide-, hydrogen sulfide-releasing) compounds that release both H2S and NO, and have IC50s for cell growth inhibition in the low nano-molar range. Methods: Compounds: Aspirin based NOSH-1, NOSH-2, NOSH-3, and NOSH-4 were synthesized and purified by us with 1H-NMR verification. Human cancer cell lines: colon (HT-29, HCT 15, SW480), breast (MCF-7, MDA-MB-231, SKBR3), pancreas (BxPC-3, MIA PaCa-2), lung (A549), prostate (LNCap), leukemia (Jurkat). Cell growth: MTT. Anti-inflammatory: paw edema induced by intraplantar injection of 100 µL of 1% carrageenan, paw volumes measured up to the tibiotarsal joint immediately prior to carrageenan injection and thereafter at 1hr intervals up to 6hrs. Drugs were administered orally 1 hr before carrageenan; COX enzyme: immunoblotting, PGE2: ELISA Results: All NOSH compounds were more effective than aspirin in inhibiting the growth of colon, breast, pancreas, prostate, lung, and leukemia cancer cell lines. The IC50s at 24h were in the range 48 nM to 6.5 µM depending on the cell line and the compound. The corresponding IC50 for aspirin was >5000 µM in all cell lines. Our lead compound NOSH-1, had a enhanced potency of >100,000-fold. NOSH-1 dose-dependently decreased the carrageenan-induced edema 1h after administration and maintained this anti-inflammatory effect throughout the experiment (up to 6h). PGE2 levels within the inflamed rat paw were also reduced by NOSH-1. Carrageenan induced both COX-1 and COX-2 expression which were dose-dependently inhibited by NOSH-1. Conclusions: NOSH compounds are a new class of anti-inflammatory agents. NOSH-1, our lead compound is very potent in inhibiting a number of different cancer cell lines of different tissue origin suggesting a tissue independent effect. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3899. doi:1538-7445.AM2012-3899