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Submitted on April 26, 2006
Accepted on November 7, 2006
Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan, and TAP Pharmaceutical Products Inc., Lake Forest, Illinois, 60045, USA
* To whom correspondence should be addressed. E-mail: maruo{at}kobe-u.ac.jp.
Context: We previously demonstrated that asoprisnil, a selective progesterone receptor modulator, induces apoptosis of cultured uterine leiomyoma cells. This study was conducted to evaluate whether asoprisnil activates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptotic pathway in cultured uterine leiomyoma and matching myometrial cells.
Objective and Methods: After subculture in phenol red-free DMEM supplemented with 10% fetal bovine serum for 120 h, cultured cells were stepped down to serum-free conditions for 24 h in the absence or presence of graded concentrations of asoprisnil. The levels of TRAIL signaling molecules and cellular inhibitors of apoptosis protein (c-IAPs) were assessed by Western blot analysis.
Results: TRAIL contents in untreated cultured leiomyoma cells were significantly (P < 0.01) lower compared with those in untreated cultured myometrial cells. There was no difference in death receptor (DR) 4 and DR5 contents between the two types of cells. Asoprisnil treatment significantly (P < 0.05) increased TRAIL, DR4, and DR5 contents in cultured leiomyoma cells in a dose-dependent manner with a cleavage of caspase-8, -7, and -3, and decreased X-linked chromosome-linked IAP (XIAP) contents. In cultured myometrial cells, however, asoprisnil treatment did not affect either TRAIL signaling molecule or c-IAP contents. The concomitant treatment with 100 ng/mL P4 significantly (P < 0.05) reversed asoprisnil-induced increase in DR4 and cleaved poly(adenosine 5'-disphophate-ribose) contents in cultured leiomyoma cells.
Conclusions: These results suggest that asoprisnil induces apoptosis of cultured leiomyoma cells by activating TRAIL-mediated apoptotic pathway and down-regulating XIAP levels in the absence of comparable effects on myometrial cells.
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