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This version published online on March 19, 2003
Endocrinology, doi:10.1210/en.2002-0180
A more recent version of this article appeared on July 1, 2003
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Submitted on December 23, 2002
Accepted on March 7, 2003

Valproic acid increases the stimulatory effect of estrogens on proliferation of human endometrial adenocarcinoma cells

Grazia Graziani1*, Lucio Tentori1, Ilaria Portarena1, Matteo Vergati1, and Pierluigi Navarra1

1 Department of Neuroscience, University of Rome "Tor Vergata", Rome, Italy (GG, LT, IP, MV).; Institute of Pharmacology, Catholic University Medical School, Rome, Italy (PN).

* To whom correspondence should be addressed. 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 {alpha} (ER-{alpha}) by suppressing gene transcription.

Since estrogens are known to increase cell proliferation of human endometrial tumors, in this study we have investigated whether treatment with VA may increase the proliferative response of human endometrial adenocarcinoma cells to 17-{beta}-estradiol (E2) through induction of ER-{alpha}. The results clearly show that VA, at concentrations of clinical interest, significantly enhanced the proliferative activity exerted by E2 in the endometrial adenocarcinoma Ishikawa cell line. Moreover, in these cells treatment with VA resulted in increased ER-{alpha} gene expression. Similar effects of VA on cell proliferation were also observed in an ER-{alpha} positive breast cancer cell line (MCF-7).

These findings indicate that VA might favor proliferation of estrogen-dependent human tumors.
Key words: estradiol • estrogen receptor • trichostatin A • histone deacetylase inhibitors • anticonvulsant drug






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