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Valproic Acid Increases the Stimulatory Effect of Estrogens on Proliferation of Human Endometrial Adenocarcinoma Cells

Department of Neuroscience (G.G., L.T., I.P., M.V.), University of Rome "Tor Vergata," 00133 Rome, Italy; Institute of Pharmacology (P.N.), Catholic University Medical School, 00168 Rome, Italy

Address all correspondence and requests for reprints to: Grazia Graziani, M.D., Department of Neuroscience, University of Rome "Tor Vergata," Via Montpellier 1, 00133 Rome, Italy. E-mail: graziani{at}uniroma2.it.

Long-term use of valproic acid (VA), a well-tolerated anticonvulsant agent widely used for treating epilepsia, has been recently shown to inhibit histone deacetylases, which in turn are involved in the regulation of the expression of estrogen receptor (ER) by suppressing gene transcription. Because estrogens are known to increase cell proliferation of human endometrial tumors, in this study we investigated whether treatment with VA may increase the proliferative response of human endometrial adenocarcinoma cells to 17-ß-estradiol through induction of ER. The results clearly show that VA, at concentrations of clinical interest, significantly enhanced the proliferative activity exerted by 17-ß-estradiol in the endometrial adenocarcinoma Ishikawa cell line. Moreover, in these cells treatment with VA resulted in increased ER gene expression. Similar effects of VA on cell proliferation were also observed in an ER-positive breast cancer cell line (MCF-7). These findings indicate that VA might favor proliferation of estrogen-dependent human tumors.

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