Non-genomic effects of progestins--inhibition of cell growth and increased intracellular levels of cyclic nucleotides.
The anti-proliferative effect of progestins was studied in human transformed cell lines from the uterine cervix (C-4I, C33A and Me-180). Progestins caused a concentration-dependent inhibition of proliferation. The maximum tested concentration (2.6-3.2 microM) inhibited C-4I cell growth by the following order of potency: progesterone (56%) > medroxyprogesterone (38%) > megestrol acetate (25%). The sensitivity, expressed as I(25) (the concentration that caused 25% inhibition of growth), showed the same order: progesterone (7.7 nM) > medroxyprogesterone (78 nM) > megestrol acetate (570 nM). The intracellular levels of cGMP and cAMP were elevated and the cellular export of these cyclic nucleotides was inhibited by a similar order of potency. The C-4I cell line was devoid of progesterone-, estrogen-, androgen- and glucocorticoid-receptors. In addition, the antiprogestins mifepristone, onapristone and ZK-112993 did not block the anti-proliferative effect of progesterone. On the other hand, antiprogestins (2.3 nM) appeared to have some progesterone-like ("mimetic") activity with inhibition of C-4I cell growth; mifepristone (11%), onapristone (12%) and ZK-112993 (16%). The observed effects of progestins and antiprogestins on C-4I cells were also presented in C33A cells (16% androgen receptor positive) and Me-180 cells (22% progesterone receptor positive, 9% androgen receptor positive and 17% glucocorticoid receptor positive). This study suggests that a non-genomic mechanism contributes to the anti-proliferative effect of progestins.
Sager
Georg
G
Department of Pharmacology, Faculty of Medicine, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway. georg_sager@fagmed.uit.no
Ørbo
Anne
A
Jaeger
Ragnhild
R
Engström
Catharina
C
D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D000242:Cyclic AMP / Q000737:chemistry*; D006152:Cyclic GMP / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D006067:Gonanes / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D015735:Mifepristone / Q000031:analogs & derivatives* / Q000494:pharmacology; D011372:Progestins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011863:Radioimmunoassay; D011987:Receptors, Steroid; D013997:Time Factors
D000970:Antineoplastic Agents; D006067:Gonanes; D006727:Hormone Antagonists; D011372:Progestins; D011987:Receptors, Steroid; C064879:ZK 112993; D015735:Mifepristone; D000242:Cyclic AMP; D006152:Cyclic GMP; C053238:onapristone