TY - JOUR T1 - Positional isomers of aspirin are equally potent in inhibiting colon cancer cell growth: Differences in mode of cyclooxygenase inhibition JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.112.201970 SP - jpet.112.201970 AU - Ravinder Kodela AU - Mitali Chattopadhyay AU - Satindra Goswami AU - Zong Yuan Gan AU - Praveen P.N. Rao AU - Kamran V. Nia AU - Carlos A. Velazquez-Martinez AU - Khosrow Kashfi Y1 - 2013/01/01 UR - http://jpet.aspetjournals.org/content/early/2013/01/24/jpet.112.201970.abstract N2 - We compared the differential effects of positional isomers of acetyl salicylic acid (o-ASA, m-ASA, and p-ASA) on COX inhibition, gastric PGE2, MDA, plasma TNFα levels, SOD activity, HT-29 cell growth inhibition, cell proliferation, apoptosis, and cell cycle progression. We also evaluated the gastric toxicity exerted by ASA isomers. All ASA isomers inhibit COX enzymes, but only the o-ASA exerted an irreversible inhibitory profile. We did not observe a significant difference between ASA isomers in their ability to decrease the in vivo synthesis of PGE2 and SOD activity. Furthermore, all isomers increased the levels of gastric MDA and TNFα when administered orally at equimolar doses. We observed a dose-dependent cell growth inhibitory effect, the order of potency was p-ASA > m-ASA ≈ o-ASA. There was a dose-dependent decrease in cell proliferation and an increase in apoptosis, with a concomitant Go/G1 arrest. The ulcerogenic profile of the three ASA isomers showed a significant difference between o-ASA (aspirin) and its two positional isomers when administered orally at equimolar doses (1 mmol/kg); the ulcer index (UI) for o-ASA indicated extensive mucosal injury (UI = 38), whereas m-ASA and p-ASA produced a significantly decreased toxic response (UI = 12 and 8 respectively) under the same experimental conditions. These results suggest that the three positional isomers of ASA exert practically the same biological profile in vitro and in vivo, but showed different safety profiles. The mechanism of gastric ulcer formation exerted by aspirin and its two isomers warrants a more detailed and thorough investigation. ER -