Gestrinone inhibits growth of human uterine leiomyoma may relate to activity regulation of ERα, Src and P38 MAPK.

Abstract

The study was to investigate the effect of gestrinone on the growth of human uterine leiomyoma cells and on the levels and activity of p38, Src and estrogen receptor alpha (ERα). Human uterine leiomyoma cells were cultured and treated with dimethylsulfoxide (DMSO) or a gestrinone concentration gradient. Morphological changes were observed and apoptosis was evaluated. Levels of p38 and phosphorylated-p38 (pp38) were assayed by enzyme-linked immunosorbent assay (ELISA). Levels of ERα and Src were analyzed using real-time RT-PCR and Western blotting. The result showed that gestrinone significantly inhibited the growth of cultured human uterine leiomyoma cells in a concentration- and time-dependent manner, with a 50% inhibitory concentration (IC(50)) value and corresponding 95% confidence intervals (CI) of 43.67 (23.46∼81.32), 27.78 (12.51∼61.68) and 15.25 (7.17∼32.43) μmol/L at 20, 40 and 60h, respectively. Compared with control-treated leiomyoma cells, gestrinone significantly reduced both the expression of ERα (P<0.05) and the levels of phospho-Ser167-ERα (P<0.05). Gestrinone also markedly suppressed the level of phospho-Tyr416-Src (P<0.05). Moreover, gestrinone significantly increased the ratio of phospho-p38/p38 mitogen-activated protein kinase (MAPK) (P<0.05). However, no significant increase in apoptosis or cell cycle arrest was observed (P>0.05) in response to the tested concentrations of 0.1 to 3.0μmol/L. As a conclusion, gestrinone suppresses the proliferation of uterine leiomyoma cells mainly by regulating the activity of ERα/Src/p38 MAPK in a concentration-dependent manner at a low concentration of 0.1∼3.0μM, but not significantly regulating apoptosis. Gestrinone opposes the growth of uterine leiomyoma through multiple genes.

• Authors: Yan Zhu, Tingting Zhang, Shuwu Xie, Ruiqin Tu, Yang Cao, Xiangjie Guo, Jieyun Zhou, Xianying Zhou, Lin Cao
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 66 Issue 8 Pg. 569-77 (Dec 2012) ISSN: 1950-6007 [Electronic] France
• PMID: 23102719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012. Published by Elsevier SAS.

Chemical References

• Estrogen Receptor alpha
• Gestrinone
• CSK Tyrosine-Protein Kinase
• src-Family Kinases
• CSK protein, human
• p38 Mitogen-Activated Protein Kinases

Topics

• Apoptosis (drug effects)
• Blotting, Western
• CSK Tyrosine-Protein Kinase
• Cell Culture Techniques
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Gestrinone (administration & dosage, pharmacology, therapeutic use)
• Humans
• In Situ Nick-End Labeling
• Leiomyoma (drug therapy, genetics, metabolism, ultrastructure)
• Microscopy, Electron, Transmission
• Molecular Structure
• Real-Time Polymerase Chain Reaction
• Time Factors
• Tumor Cells, Cultured
• Uterine Neoplasms (drug therapy, genetics, metabolism, ultrastructure)
• p38 Mitogen-Activated Protein Kinases (genetics, metabolism)
• src-Family Kinases (genetics, metabolism)