The differential cell signaling effects of two positional isomers of the anticancer NO-donating aspirin

Amy Hua, Gerardo Mackenzie, Basil Rigas

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

We studied the mechanism by which the para and meta positional isomers of nitric oxide-donating aspirin (NO-ASA) inhibit human colon cancer cell growth. These compounds are promising chemopreventive agents and represent a broader class of novel drugs. The two isomers differ drastically in their 24-h IC 50s for cell growth, which are 12 μM for p-NO-ASA and 230 μM for m-NO-ASA. We examined their effects on cell signaling cascades, including predominantly the mitogen activated protein kinases (MAPKs). The principal differences between the two isomers were: a) p-NO-ASA exerts its effect earlier than m-NO-ASA; b) the predominant effect of m-NO-ASA is on ERK1/2 and Akt; whereas that of p-NO-ASA is on JNK1/2, while both activate p38, with p-NO-ASA showing a stronger and earlier effect; c) ATF-2 is more responsive to m-NO-ASA and c-Jun to p-NO-ASA; d) both isomers seem to have similar effects on AP-1 binding, the main difference between them being the timing of the effect; p-NO-ASA's effect is early and m-NOASA's is late; e) p-NO-ASA has an earlier and stronger effect on p21, while m-NO-ASA's effect occurs later and is weaker; and f) cell cycle changes follow the effect on p21 expression. Our findings underscore the role of positional isomerism in modulating the pharmacological effects of drugs and have potentially important implications for the further development of these chemoprevention agents.

Original languageEnglish (US)
Pages (from-to)837-844
Number of pages8
JournalInternational Journal of Oncology
Volume35
Issue number4
DOIs
StatePublished - Oct 1 2009
Externally publishedYes

Keywords

  • Cancer prevention
  • Mitogen activated protein kinases
  • Nitric oxide-donating aspirin
  • P21
  • Positional isomerism

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'The differential cell signaling effects of two positional isomers of the anticancer NO-donating aspirin'. Together they form a unique fingerprint.

  • Cite this