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 lines. It is also known to be an anti-inflammatory agent acting by the inhibition of prostaglandin (PG) synthesis. To evaluate a clinical application as antitumoral agent, we have studied whether antiproliferative effect of indomethacin in breast cancer is related to its action on the prostaglandin production. We have observed that indomethacin as well as PGE1, PGE2, PGD2, and PGI2 inhibited the proliferation of MCF-7 breast cancer cells. As breast carcinomas were described to secrete mainly PGE2, we studied the effect of PGE2 on MCF-7 cells. These cells contain two types of binding sites for PGE2: high-affinity (Kd = 0.2 nM) and low-affinity (Kd = 20 nM) receptors. In this cell line, indomethacin and PGE2 inhibitory effects were additive. In addition, we showed that PGE2 increased the cAMP level in MCF-7 cells 30-fold (p < 0.001) while indomethacin did not change basal cAMP accumulation. Like for combination PGE2/indomethacin, the inhibitory effects of a cAMP analog (8-Br-cAMP) and indomethacin were additive. In conclusion, indomethacin inhibits the MCF-7 growth in specific manner independently of PG synthesis, PG action and cAMP accumulation.
Planchon
P
P
Institut d'Oncologie Cellulaire et Moléculaire Humaine, Hôpital Avicenne, Bobigny, France.
Veber
N
N
Magnien
V
V
Prévost
G
G
Starzec
A B
AB
Israël
L
L
D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D011453:Prostaglandins / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D011453:Prostaglandins; D000242:Cyclic AMP; D007213:Indomethacin