PT  - JOURNAL ARTICLE
AU  - Paolo Ricchi
AU  - Antonella Di Palma
AU  - Tiziana Di Matola
AU  - Anna Apicella
AU  - Rosaria Fortunato
AU  - Raffaele Zarrilli
AU  - Angela Maria Acquaviva
TI  - <strong>Aspirin Protects Caco-2 Cells from Apoptosis after Serum Deprivation
 through the Activation of a Phosphatidylinositol
 3-Kinase/AKT/p21</strong><sup><em>Cip</em>/<strong><em>WAF</em>1</strong></sup>Pathway
AID  - 10.1124/mol.64.2.407
DP  - 2003 Aug 01
TA  - Molecular Pharmacology
PG  - 407--414
VI  - 64
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/64/2/407.short
4100  - http://molpharm.aspetjournals.org/content/64/2/407.full
SO  - Mol Pharmacol2003 Aug 01; 64
AB  - Our previous studies indicated that millimolar doses of aspirin induced growth arrest and resistance to anticancer drug treatment in Caco-2 cells. The present study was designed to better elucidate at the molecular level the effect of aspirin treatment on pathways that regulate cell death during serum withdrawal. Caco-2 cells were cultured under serum deprivation in the presence or absence of aspirin. Effects on cell cycle, phosphatidylinositol 3-kinase (PI3-kinase) and mitogen-activated protein (MAP) kinase pathways were investigated. We found that aspirin, but not the selective cyclooxygenase-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398); prevented apoptosis and G2/M transition after prolonged Caco-2 cells serum deprivation. Aspirin-dependent inhibition of apoptosis and G2/M transition was prevented by treatment with the PI3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), but not with the MAP kinase kinase inhibitor 2′-amino-3′-methoxyflavone (PD98059). The effects of aspirin were mediated at molecular levels, through activation of PI3-kinase/AKT pathway and increase in the p21Cip/WAF1 level. The ability of aspirin to activate AKT protein was observed also in presence of etoposide cotreatment. Our data indicate a new intracellular target of aspirin with potential clinical impact for treatment schedules involving both anticancer agents and aspirin in malignancies.