2-methoxyestradiol strongly inhibits human uterine sarcomatous cell growth.
OBJECTIVE
The objective was to test the hypothesis that uterine sarcomatous cells are hormone-sensitive. We included 2-methoxyestradiol, an endogenous metabolite of estradiol with antiproliferative properties.


METHODS
Proliferation assays assessed the effects of estradiol, progesterone, tamoxifen, raloxifen, [D-Trp(6)]leuteinizing hormone-releasing hormone (LHRH), ICI 182,780 (faslodex or fulvestrant), and 2-methoxyestradiol on cell growth of a cell line derived from uterine carcinosarcoma, but consisting solely of mesenchymal cells (SK-UT-1). Morphological changes of SK-UT-1 cells after exposure to 2-methoxyestradiol were evaluated and fluorescence immunohistochemistry for tubulin was used to detect changes in the mitotic spindle. Flow cytometry was used to assess the influence of 2-methoxyestradiol on the SK-UT-1 cell cycle as well as the role of p53 in apoptosis.


RESULTS
Cell proliferation analysis revealed that SK-UT-1 cells were stimulated by progesterone, tamoxifen, and [D-Trp(6)]LHRH. Cells were insensitive to estradiol, raloxifen, and ICI 182,780. Inhibition occurred after exposure to 2-methoxyestradiol and was accompanied by a threefold increase in the G2/M population, with a concomitant decrease in the G1 population, as shown by cell cycle analysis. SK-UT-1 cells exposed to 2-methoxyestradiol showed morphological changes indicative of apoptosis. Examination of signaling pathways that mediate 2-methoxyestradiol-induced apoptosis showed p53-independent growth inhibition. The inhibition of SK-UT-1 cell growth by arresting the cells during G2/M progression could be attributed to interference with the microtubule system, as determined by fluorescence immunohistochemistry.


CONCLUSIONS
The stimulatory effect of progesterone, tamoxifen, and [D-Trp(6)]LHRH suggests that uterine sarcomatous cells are hormone-sensitive. Our finding that 2-methoxyestradiol-mediated growth inhibition of uterine sarcomatous cells occurred in a p53-independent manner may have considerable clinical significance. The inadequate armature against uterine sarcomas and the limited toxicity of 2-methoxyestradiol may render these observations especially important.
Amant
Frederic
F
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium. Frederic.Amant@uz.kuleuven.ac.be
Lottering
Mona Liza
ML
Joubert
Annie
A
Thaver
Veneesha
V
Vergote
Ignace
I
Lindeque
B G
BG
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D002296:Carcinosarcoma / Q000188:drug therapy / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000473:pathology*; D011374:Progesterone / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D017329:Triptorelin Pamoate / Q000494:pharmacology; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000473:pathology*
D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D017329:Triptorelin Pamoate; D013629:Tamoxifen; C037233:2-methylestradiol; D000077267:Fulvestrant; D020849:Raloxifene Hydrochloride; D011374:Progesterone; D004958:Estradiol