title: 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 (H(2)S) can increase mucosal defense mechanisms has led to the development of NO- and H(2)S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH-aspirin, which is an NO- and H(2)S-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.
authors.affiliation: Department of Physiology, Pharmacology, and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, NY 10031, USA.
authors.forename: Mitali
authors.initials: M
authors.lastname: Chattopadhyay
authors.forename: Ravinder
authors.initials: R
authors.lastname: Kodela
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Olson
authors.forename: Khosrow
authors.initials: K
authors.lastname: Kashfi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009566:Nitrates / Q000737:chemistry / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: C571898:4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 2-((4-(nitrooxy)butanoyl)oxy)benzoate; D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D004220:Disulfides; D009566:Nitrates; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin; D006862:Hydrogen Sulfide