Gonadotropin-releasing hormone type II antagonists induce apoptotic cell death in human endometrial and ovarian cancer cells in vitro and in vivo.

Abstract

In human endometrial and ovarian cancers, gonadotropin-releasing hormone type I (GnRH-I), GnRH-II, and their receptors are parts of a negative autocrine regulatory system of cell proliferation. Based on a tumor-specific signal transduction, GnRH-I and GnRH-II agonists inhibit the mitogenic signal transduction of growth factor receptors and related oncogene products associated with tyrosine kinase activity via activation of a phosphotyrosine phosphatase resulting in down-regulation of cancer cell proliferation. Induction of apoptosis is not involved. In this study, we show that treatment of human endometrial and ovarian cancer cells with GnRH-II antagonists results in apoptotic cell death via dose-dependent activation of caspase-3. The antitumor effects of the GnRH-II antagonists could be confirmed in nude mice. GnRH-II antagonists inhibited the growth of xenotransplants of human endometrial and ovarian cancers in nude mice significantly, without any apparent side effects. Thus, GnRH-II antagonists seem to be suitable drugs for an efficacious and less toxic endocrine therapy for endometrial and ovarian cancers.

• Authors: Stefanie Fister, Andreas R Günthert, Günter Emons, Carsten Gründker
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 4 Pg. 1750-6 (Feb 15 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17308117 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GNRHR protein, human
• GNRHR2 protein, human
• Receptors, LHRH
• Gonadotropin-Releasing Hormone
• LHRH, His(5)-Trp(7)-Tyr(8)-
• Pertussis Toxin
• Caspase 3

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Interactions
• Endometrial Neoplasms (drug therapy, metabolism, pathology)
• Enzyme Activation (drug effects)
• Female
• Gonadotropin-Releasing Hormone (analogs & derivatives, antagonists & inhibitors, pharmacology)
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Nude
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Pertussis Toxin (pharmacology)
• Receptors, LHRH (metabolism)
• Xenograft Model Antitumor Assays