title: Positional isomerism markedly affects the growth inhibition of colon cancer cells by nitric oxide-donating aspirin in vitro and in vivo.
abstract: NO-donating aspirin (NO-ASA), a novel pharmacological agent currently undergoing clinical testing, consists of ASA to which a nitrate group is covalently linked via a spacer molecule. We synthesized the three positional isomers of NO-ASA with respect to the -CH(2)ONO(2) group (ortho, meta, and para) and examined whether this isomerism affects the biological activity of NO-ASA on HT-29 human colon cancer cells. The ortho- and para-isomers showed similar IC(50) values (1-5 microM) for cell growth inhibition over 72 h, whereas the IC(50) of the meta-isomer was 200 to 500 microM. The ortho- and para-isomers inhibited cell proliferation more potently than the meta-isomer. All three induced apoptosis but the ortho- and para-isomers also induced atypical cells (they maintain their shape but have diminished or absent nuclear material). Treatment for 3 weeks of Min (Apc(min)(/+)) mice, a model of intestinal cancer, with equimolar amounts of meta- and para-NO-ASA decreased the number of tumors in the small intestine by 36 and 59% (P < 0.01), respectively, compared with vehicle-treated controls, thus confirming their in vitro differences in potency. A structure-activity study of the three isomers revealed that substituting an aliphatic for the aromatic spacer or removing the -ONO(2) group profoundly diminished NO-ASA's ability to inhibit cell growth, whereas removal of the acetyl group on the ASA moiety did not affect cell growth inhibition. Thus, positional isomerism is critical for the pharmacological properties of NO-ASA against colon cancer and it should be taken into consideration in rational drug design.
authors.affiliation: Division of Cancer Prevention, Department of Medicine, SUNY at Stony Brook, Stony Brook, NY 11794-8160, USA.
authors.forename: Khosrow
authors.initials: K
authors.lastname: Kashfi
authors.forename: Simona
authors.initials: S
authors.lastname: Borgo
authors.forename: Jennie L
authors.initials: JL
authors.lastname: Williams
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Jianjun
authors.initials: J
authors.lastname: Gao
authors.forename: Athanasios
authors.initials: A
authors.lastname: Glekas
authors.forename: Francesca
authors.initials: F
authors.lastname: Benedini
authors.forename: Piero
authors.initials: P
authors.lastname: Del Soldato
authors.forename: Basil
authors.initials: B
authors.lastname: Rigas
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D007536:Isomerism; D009566:Nitrates / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D013329:Structure-Activity Relationship
chemical_list: D006131:Growth Inhibitors; C488176:N-acetyl-S-(alpha-methyl-4-(2-methylpropyl)benzeneacetyl)cysteine 4-(nitrooxy)butyl ester; D009566:Nitrates; D020030:Nitric Oxide Donors; D018809:Proliferating Cell Nuclear Antigen; D009569:Nitric Oxide; D001241:Aspirin