Strong cytotoxic effect of the bradykinin antagonist BKM-570 in ovarian cancer cells--analysis of the molecular mechanisms of its antiproliferative action.

Abstract

The standard chemotherapy for epithelial ovarian cancer (EOC) patients is currently a combination of taxane and platinum. However, most EOC patients still suffer relapses, and there is an immediate need for the development of novel and more effective therapeutic modalities against this deadly disease. Recently, the nonpeptide bradykinin (BK) antagonist 2,3,4,5,6-pentafluorocinnamoyl-(o-2,6-dichlorobenzyl)-l-tyrosine-N-(4-amino-2,2,6,6-tetramethyl-piperidyl) amide (BKM-570) was shown to cause impressive growth inhibition of lung and prostate tumors, displaying superior in vivo inhibitory effects than convential chemotherapeutic drugs. Here, we investigated BKM-570 cytotoxic effects in two EOC cell lines, derived from different EOC histopathologies: a clear cell carcinoma (TOV-21), and an endometrioid carcinoma (TOV-112). We showed that BKM-570 effectively inhibited the growth of ovarian cancer cells, as its cytotoxic effects were comparable to those of cisplatin, and were independent of the functional status of BK receptors. Moreover, BKM-570 synergized with cisplatin in inhibiting EOC cell growth. To better understand the molecular mechanisms of the antiproliferative action of this BK antagonist in EOC cells, we performed gene expression profiling in TOV-21 and TOV-112 cells following treatment with 10 μM BKM-570 for 24 h. BKM-570 displayed similar cytotoxic effects in the two cell lines analyzed, as genes with previously shown involvement in apoptosis/antiapoptosis and cell adhesion were proportionally upregulated and downregulated in both cell lines, whereas genes involved in basic cellular mechanisms, including cell growth and maintenance, metabolism, cell cycle control, inflammatory and immune response, signal transduction, protein biosynthesis, transcription regulation, and transport, were predominantly downregulated upon treatment. Our data are indicative of the therapeutic potential of BKM-570 and related compounds in EOC management.

• Authors: Stephanie Jutras, Magdalena Bachvarova, Mamadou Keita, Jean-Loup Bascands, Anne-Marie Mes-Masson, John M Stewart, Lajos Gera, Dimcho Bachvarov
• Journal: The FEBS journal (FEBS J) Vol. 277 Issue 24 Pg. 5146-60 (Dec 2010) ISSN: 1742-4658 [Electronic] England
• PMID: 21078129 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Validation Study)
• Copyright: © 2010 The Authors Journal compilation © 2010 FEBS.

Chemical References

• Antineoplastic Agents
• BKM-570
• Receptors, Bradykinin
• Tyrosine
• Cisplatin
• Bradykinin

Topics

• Antineoplastic Agents (pharmacology)
• Bradykinin (antagonists & inhibitors)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (pharmacology)
• Drug Screening Assays, Antitumor
• Drug Synergism
• Female
• Gene Expression Profiling
• Humans
• Oligonucleotide Array Sequence Analysis
• Ovarian Neoplasms (metabolism, pathology)
• Receptors, Bradykinin (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tyrosine (analogs & derivatives, pharmacology)