1. Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Galpha/Gbetagamma protein complex
- Author
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Grégoire P, Prévost, Marie O, Lonchampt, Susan, Holbeck, Samir, Attoub, Daniel, Zaharevitz, Mike, Alley, John, Wright, Marie C, Brezak, Hélène, Coulomb, Ann, Savola, Marion, Huchet, Sophie, Chaumeron, Quang-Dé, Nguyen, Patricia, Forgez, Erik, Bruyneel, Mark, Bracke, Eric, Ferrandis, Pierre, Roubert, Danièle, Demarquay, Christian, Gespach, and Philip G, Kasprzyk
- Subjects
Cell Cycle ,GTP-Binding Protein beta Subunits ,Imidazoles ,Antineoplastic Agents ,Apoptosis ,HL-60 Cells ,Cell Growth Processes ,Heterotrimeric GTP-Binding Proteins ,Xenograft Model Antitumor Assays ,GTP-Binding Protein alpha Subunits ,Mice ,Cell Line, Tumor ,GTP-Binding Protein gamma Subunits ,Animals ,Humans ,Female ,Neoplasm Invasiveness ,Cysteine ,Drug Screening Assays, Antitumor - Abstract
A large number of hormones and local agonists activating guanine-binding protein-coupled receptors (GPCR) play a major role in cancer progression. Here, we characterize the new imidazo-pyrazine derivative BIM-46174, which acts as a selective inhibitor of heterotrimeric G-protein complex. BIM-46174 prevents the heterotrimeric G-protein signaling linked to several GPCRs mediating (a) cyclic AMP generation (Galphas), (b) calcium release (Galphaq), and (c) cancer cell invasion by Wnt-2 frizzled receptors and high-affinity neurotensin receptors (Galphao/i and Galphaq). BIM-46174 inhibits the growth of a large panel of human cancer cell lines, including anticancer drug-resistant cells. Exposure of cancer cells to BIM-46174 leads to caspase-3-dependent apoptosis and poly(ADP-ribose) polymerase cleavage. National Cancer Institute COMPARE analysis for BIM-46174 supports its novel pharmacologic profile compared with 12,000 anticancer agents. The growth rate of human tumor xenografts in athymic mice is significantly reduced after administration of BIM-46174 combined with either cisplatin, farnesyltransferase inhibitor, or topoisomerase inhibitors. Our data validate the feasibility of targeting heterotrimeric G-protein functions downstream the GPCRs to improve anticancer chemotherapy.
- Published
- 2006