Details

Autor(en) / Beteiligte

• Prevost, Gregoire P
• Lonchampt, Marie O
• Holbeck, Susan
• Attoub, Samir
• Zaharevitz, Daniel
• Alley, Mike
• Wright, John
• Brezak, Marie C
• Coulomb, Helene
• Savola, Ann
• Huchet, Marion
• Chaumeron, Sophie
• Nguyen, Quang-De
• gez, Patricia
• Bruyneel, Erik
• Bracke, Mark
• Ferrandis, Eric
• Roubert, Pierre
• Demarquay, Daniele
• Gespach, Christian
• Kasprzyk, Philip G

Titel

Anticancer Activity of BIM-46174, a New Inhibitor of the Heterotrimeric G alpha /G beta gamma Protein Complex

Ist Teil von

• Cancer research (Chicago, Ill.), 2006-09, Vol.66 (18), p.9227-9234

Erscheinungsjahr

2006

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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 (G alpha s), (b) calcium release (G alpha q), and (c) cancer cell invasion by Wnt-2 frizzled receptors and high-affinity neurotensin receptors (G alpha o/i and G alpha q). 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. (Cancer Res 2006; 66(18): 9227-34)