title: Positional isomerism markedly affects the growth inhibition of colon cancer cells by NOSH-aspirin: COX inhibition and modeling.
abstract: We recently reported the synthesis of NOSH-aspirin, a novel hybrid that releases both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e. ortho-NOSH-aspirin (o-NOSH-aspirin). In the present study, we compared the effects of the positional isomers of NOSH-ASA (o-NOSH-aspirin, m-NOSH-aspirin and p-NOSH-aspirin) to that of aspirin on growth of HT-29 and HCT 15 colon cancer cells, belonging to the same histological subtype, but with different expression of cyclooxygenase (COX) enzymes; HT-29 express both COX-1 and COX-2, whereas HCT 15 is COX-null. We also analyzed the effect of these compounds on proliferation and apoptosis in HT-29 cells. Since the parent compound aspirin, inhibits both COX-1 and COX-2, we also evaluated the effects of these compounds on COX-1 and COX-2 enzyme activities and also performed modeling of the interactions between the positional isomers of NOSH-aspirin and COX-1 and COX-2 enzymes. We observed that the three positional isomers of NOSH aspirin inhibited the growth of both colon cancer cell lines with IC50s in the nano-molar range. In particular in HT-29 cells the IC50s for growth inhibition were: o-NOSH-ASA, 0.04±0.011 µM; m-NOSH-ASA, 0.24±0.11 µM; p-NOSH-ASA, 0.46±0.17 µM; and in HCT 15 cells the IC50s for o-NOSH-ASA, m-NOSH-ASA, and p-NOSH-ASA were 0.062 ±0.006 µM, 0.092±0.004 µM, and 0.37±0.04 µM, respectively. The IC50 for aspirin in both cell lines was >5mM at 24h. The reduction of cell growth appeared to be mediated through inhibition of proliferation, and induction of apoptosis. All 3 positional isomers of NOSH-aspirin preferentially inhibited COX-1 over COX-2. These results suggest that the three positional isomers of NOSH-aspirin have the same biological actions, but that o-NOSH-ASA displayed the strongest anti-neoplastic potential.
authors: Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031, United States.
authors: Federica
authors: F
authors: Vannini
authors: Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031, United States.
authors: Mitali
authors: M
authors: Chattopadhyay
authors: Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031, United States.
authors: Ravinder
authors: R
authors: Kodela
authors: School of Pharmacy Health Science Campus, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1.
authors: Praveen P N
authors: PPN
authors: Rao
authors: Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031, United States; Avicenna Pharmaceuticals Inc., New York, NY 10019, United States. Electronic address: kashfi@med.cuny.edu.
authors: Khosrow
authors: K
authors: Kashfi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015870:Gene Expression; D019073:HT29 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D009566:Nitrates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012756:Sheep; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
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; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D001241:Aspirin; D006862:Hydrogen Sulfide
keywords: Aspirin; Colon cancer; Cyclooxygenase; Hydrogen sulfide; Molecular docking; NSAIDs; Nitric oxide