Positional isomerism markedly affects the growth inhibition of colon cancer cells by NOSH-aspirin: COX inhibition and modeling

Redox Biology
Federica VanniniKhosrow Kashfi

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 growt...Continue Reading

References

Mar 7, 2003·The New England Journal of Medicine·Robert S SandlerRichard Schilsky
Jul 20, 2007·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·John L WallaceGary R Martin
May 19, 2009·Gastroenterology Clinics of North America·Stefano Fiorucci
Jan 3, 2012·Biochemical Pharmacology·Mitali ChattopadhyayKhosrow Kashfi
Jun 30, 2012·Journal of the American Chemical Society·Milos R FilipovicIvana Ivanović-Burmazović
Jan 26, 2013·The Journal of Pharmacology and Experimental Therapeutics·Ravinder KodelaKhosrow Kashfi
Jan 16, 2014·The Journal of Biological Chemistry·Shu XuLawrence J Marnett
Jun 15, 2014·Nitric Oxide : Biology and Chemistry·Maria Letizia Lo FaroMatthew Whiteman
Dec 30, 2014·Nitric Oxide : Biology and Chemistry·Miriam M Cortese-KrottMartin Feelisch

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Methods Mentioned

BETA
xenografts
ELISA
FACS
flow cytometry
acetylation

Software Mentioned

CHARMm
Flow Jo
Discovery Studio ( DS ) Client
CDOCKER

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