Inhibition of leiomyoma cell proliferation in vitro by genistein and the protein tyrosine kinase inhibitor TKS050.

Abstract

OBJECTIVE:

To determine the potency of TKS050, a new epidermal growth factor receptor (EGFR) inhibitor and genistein, a naturally occurring protein tyrosine kinase inhibitor, to inhibit leiomyoma cell proliferation in vitro.

DESIGN:

Establishment of paired cultures of leiomyoma and normal myometrial samples.

SETTING:

University clinical research laboratory.

PATIENT(S):

Hysterectomy specimens from premenopausal women affected by uterine leiomyomas.

INTERVENTION(S):

The suppressive effect of TKS050 and genistein on the cells, before and after steroidal hormone treatment, was examined.

MAIN OUTCOME MEASURE(S):

Cell proliferation, recovery after treatment, cell cycle analysis, and immunochemical analysis of relevant proteins were performed.

RESULT(S):

TKS050 (2 micromol/L) and genistein (50 micromol/L) completely suppressed leiomyoma cell proliferation, and the cells did not recover after cessation of treatment. TKS050 induced cell cycle arrest and apoptosis in a dose- and time-dependent manner. Cells accumulated in the G(0)/G(1) phase of the cell cycle at the expense of the S and G(2)+M phases. Treatment of cells with TKS050 resulted in a dose-dependent inhibition of EGFR autophosphorylation and of phosphorylated signal transducer and activator of transcription 3 (Stat3). Genistein inhibited the phosphorylated Stat3 but did not affect EGFR autophosphorylation. The inhibitory effects of TKS050 or genistein were unaffected by the presence of physiologic concentrations of estradiol-17beta.

CONCLUSION(S):

Leiomyoma cell growth is effectively blocked by TKS050 and genistein. The inhibitory action of newly developed and natural inhibitors derived from diet may be useful as a possible alternative therapy for leiomyomas.

• Authors: Asher Shushan, Hannah Ben-Bassat, Eyal Mishani, Neri Laufer, Benjamine Y Klein, Nathan Rojansky
• Journal: Fertility and sterility (Fertil Steril) Vol. 87 Issue 1 Pg. 127-35 (Jan 2007) ISSN: 1556-5653 [Electronic] United States
• PMID: 17074332 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• N-(4-((3,4-dichloro-6-fluoro-phenyl)amino)quinazoline-6-yl)-2-chloroacetamide
• Quinazolines
• Genistein
• Protein-Tyrosine Kinases

Topics

• Antineoplastic Agents (administration & dosage)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Female
• Genistein (administration & dosage)
• Humans
• Leiomyoma (metabolism, pathology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Quinazolines (administration & dosage)
• Tumor Cells, Cultured
• Uterine Neoplasms (metabolism, pathology)