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Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Galpha/Gbetagamma protein complex
- Source :
- Cancer research. 66(18)
- Publication Year :
- 2006
-
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.
- 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
Subjects
Details
- ISSN :
- 00085472
- Volume :
- 66
- Issue :
- 18
- Database :
- OpenAIRE
- Journal :
- Cancer research
- Accession number :
- edsair.pmid..........e0d5e541f3696ee2548f42b26dff91bb