EVIDENCE FOR SEPARATE MECHANISMS OF ANTIPROLIFERATIVE ACTION OF INDOMETHACIN AND PROSTAGLANDIN ON MCF-7 BREAST-CANCER CELLS

Indomethacin is reported to decrease the growth of many tumour cell li nes. It is also known to be an anti-inflammatory agent acting by the i nhibition of prostaglandin (PG) synthesis. To evaluate a clinical appl ication as antitumoral agent, we have studied whether antiproliferativ e effect of indomethacin in breast cancer is related to its action on the prostaglandin production. We have observed that indomethacin as we ll as PGE(1), PGE(2), PGD(2), and PGI(2) inhibited the proliferation o f MCF-7 breast cancer cells. As breast carcinomas were described to se crete mainly PGE(2), we studied the effect of PGE(2) on MCF-7 cells. T hese cells contain two types of binding sites for PGE(2): high-affinit y (Kd = 0.2 nM) and low-affinity (Kd = 20 nM) receptors. In this cell line, indomethacin and PGE(2) inhibitory effects were additive. In add ition, we showed that PGE(2) increased the cAMP level in MCF-7 cells 3 0-fold (p<0.001) while indomethacin did not change basal cAMP accumula tion. Like for combination PGE(2)/indomethacin, the inhibitory effects of a cAMP analog (8-Br-cAMP) and indomethacin were additive. In concl usion, indomethacin inhibits the MCF-7 growth in specific manner indep endently of PG synthesis, PG action and cAMP accumulation.