Antitumor effects of BMS-777607 on ovarian cancer cells with constitutively activated c-MET.

Abstract

OBJECTIVE:

Tyrosine-protein kinase MET (c-MET) has been reported to be a prognostic marker and suitable therapeutic target for ovarian cancer. BMS-777607, a small molecule, can inhibit MET and other protein kinase activities. The present study was conducted to investigate the mechanism of action and antitumor effect of BMS-777607 on ovarian cancer cells with constitutively activated c-MET.

MATERIALS AND METHODS:

Ovarian cancer cells with constitutively activated c-MET were first identified through Western blot analysis. Bio-behaviors, including signal transduction, proliferation, apoptosis, and migration, of the cells with constitutively activated c-MET were evaluated after BMS-777607 treatment. Liu's stain and immunological staining of α-tubuline were performed to evaluate the ploidy of the cells. A xenograft mouse model was also used to evaluate the antitumor effects of BMS-777607 on ovarian cancer cells with constitutively activated c-MET.

RESULTS:

BMS-777607 could induce the highest inhibition of cell growth in ovarian cancer cells constitutively expressing c-MET. Treating SKOV3 cells with BMS-777607 could reduce c-MET activation and inhibit downstream cell signaling, thus causing cell apoptosis and polyploidy as well as cell cycle and cell migration inhibition. This molecule also inhibited tumor growth in a mouse xenograft model of SKOV3 ovarian cancer cells in vivo.

CONCLUSION:

BMS-777607 exhibits antitumor effects on ovarian cancer cells that constitutively express c-MET through c-MET signaling blockade and the inhibition of Aurora B activity. Combination treatments to enhance the effects of BMS-777607 warrant investigation in the future.

• Authors: Chao-Chih Wu, Chia-Sui Weng, Yun-Ting Hsu, Chih-Long Chang
• Journal: Taiwanese journal of obstetrics & gynecology (Taiwan J Obstet Gynecol) Vol. 58 Issue 1 Pg. 145-152 (Jan 2019) ISSN: 1875-6263 [Electronic] China (Republic : 1949- )
• PMID: 30638469 (Publication Type: Journal Article)
• Copyright: Copyright © 2018. Published by Elsevier B.V.

Chemical References

• Aminopyridines
• Antineoplastic Agents
• N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
• Pyridones
• MET protein, human
• Proto-Oncogene Proteins c-met
• Aurora Kinase B

Topics

• Aminopyridines (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Aurora Kinase B (metabolism)
• Blotting, Western
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Female
• Humans
• Mice
• Molecular Targeted Therapy
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Phosphorylation
• Proto-Oncogene Proteins c-met (metabolism)
• Pyridones (pharmacology)
• Signal Transduction (drug effects)