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Submitted on November 1, 2005
Accepted on January 26, 2006
Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan, and TAP Pharmaceutical Products Inc., Lake Forest, USA
* To whom correspondence should be addressed. E-mail: maruo{at}kobe-u.ac.jp.
Context: Asoprisnil, a selective progesterone receptor modulator (SPRM) with mixed progesterone agonist/antagonist activity, reduces uterine leiomyoma volume in a dose dependent manner in the presence of follicular phase estrogen concentrations. The evidence from clinical studies suggests that asoprisnil may directly target the uterine leiomyomata.
Objective and Methods: The present study evaluated the effects of asoprisnil on cell proliferation, the expression of apoptosis-related proteins and apoptosis in cultured human uterine leiomyoma cells and matched normal myometrial cells. Progesterone receptor (PR)-A and PR-B expression in the two types of cells were comparatively evaluated. Cell proliferation, proliferating cell nuclear antigen (PCNA)-positive rate, and TUNEL-positive rate were assessed by MTS assay, immunocytochemistry, and TUNEL assay, respectively. The expression of apoptosis-related proteins and PR was assessed by Western blot analysis.
Results: Compared with untreated cultures, asoprisnil decreased the number of viable cultured cells, the PCNA-positive rate, and PCNA protein expression in cultured leiomyoma cells. Asoprisnil increased the TUNEL-positive rate, cleaved caspase-3, and cleaved poly(adenosine 5'-diphosphate-ribose) polymerase expression, and decreased Bcl-2 protein expression in cultured leiomyoma cells. These effects were dose- and time-dependent. In cultured myometrial cells, however, asoprisnil did not affect cell proliferation and apoptosis. PR-B expression was elevated in cultured leiomyoma cells compared with cultured myometrial cells, whereas no differences in PR-A expression were noted between the two types of cells.
Conclusions: These results show that asoprisnil inhibits proliferation and induces apoptosis in cultured uterine leiomyoma cells in the absence of comparable effects on cultured normal myometrial cells, suggesting a cell type-specific effect.
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