SYNERGISTIC EFFECTS OF 8-CHLOROCYCLIC-AMP AND RETINOIC ACID ON INDUCTION OF APOPTOSIS IN EWINGS-SARCOMA CHP-100 CELLS

The enhanced expression of the regulatory subunit of cyclic AMP (cAMP) -dependent protein kinase type I, RIalpha, has been correlated with ca ncer cell growth. Retinoic acid (RA) has been shown to play an importa nt role in the regulation of proliferation and differentiation in neop lastic cells, In the present study, the effects of cAMP analogue 8-chl orocyclic-AMP (8-Cl-cAMP) and RA (both singly and combined) on growth inhibition and apoptosis in Ewing's sarcoma CHP-100 cells were evaluat ed. The inhibitory effects of 8-Cl-cAMP and RA (9-cis-RA, 13-cis-RA, a nd all-trans-RA) on cell viability were time and dose related. The deg ree of growth inhibition induced by 9-cis-RA was the greatest among al l of the RA analogues (13-cis-RA and all-trans-RA) examined. The combi ned effects of 8-Cl-cAMP and RA on the induction of growth arrest at t he G(0)-G(1) stage of the cell cycle, apoptosis, down-regulation of RI alpha, and cleavage of poly(ADP-ribose) polymerase were synergistic. I n conclusion, it is clear that RA and 8-Cl-cAMP act in a synergistic f ashion and have potential for combination chemotherapy for the treatme nt of malignant disease.