Anticancer Activity of BIM-46174, a New Inhibitor of the Heterotrimeric Gα/Gβγ Protein Complex

Prevost, Grégoire; Lonchampt, M. O.; Holbeck, Susan L.; Attoub, Samir; Zaharevitz, Daniel; Alley, Mike; Wright, John W.; Brezak, Marie C.; Coulomb, Hélène; Savola, Ann; Huchet, Marion; Chaumeron, Sophie; Nguyen, Quang-Dé; Forgez, Patricia; Bruyneel, Erik; Bracke, Mark; Ferrandis, Eric; Roubert, Pierre; Demarquay, Danièle; Gespach, Christian; Kasprzyk, Philip G.

doi:10.1158/0008-5472.can-05-4205

Cited by 58 publications

(71 citation statements)

References 44 publications

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“…Thus, whether or not G␤␥ activates PAK1 and P-Rex1 to promote metastasis is unclear. In addition, blocking G␤␥ function by a peptide derived from the carboxyl terminus of ␤-adrenergic receptor kinase-1 (␤ARK1ct) or BIM-46174, an inhibitor of the G␣/G␤␥ complex, suppressed tumor formation and growth (Bookout et al, 2003;Prévost et al, 2006); however, whether blockade of G␤␥ suppresses cancer metastasis is unknown. Thus, it remains uncertain whether G␤␥ itself directly participates in cancer metastasis and, if it does, how G␤␥ signaling controls chemotactic cancer cell movement.…”

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confidence: 99%

Gβγ Signaling Promotes Breast Cancer Cell Migration and Invasion

Kirui

Xie

Wolff

et al. 2010

J Pharmacol Exp Ther

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Signaling through G protein-coupled receptors (GPCRs) promotes breast cancer metastasis. G proteins convey GPCR signals by dissociating into G␣ and G␤␥ subunits. The aim of the present study was to determine whether blockade of G␤␥ signaling suppresses breast cancer cell migration and invasion, which are critical components of metastasis. Conditioned media (CM) of NIH-3T3 fibroblasts are widely used as chemoattractants in in vitro cancer metastasis studies. Expression of a G␤␥ scavenger peptide attenuated NIH-3T3 CM-induced migration and invasion of both metastatic breast cancer MDA-MB-231 and MDA-MB-436 cells by 40 to 50% without effects on cell viability. Migration and invasion of cells in response to NIH-3T3 CM were also blocked by 8-(4,5,6-trihydroxy-3-oxo-3H-xanthen-9-yl)-1-naph-thalene-carboxylic acid) (M119K), a G␤␥ inhibitor, with maximum inhibition exceeding 80% and half-maximal inhibitory concentration (IC 50 ) values of 1 to 2 M.M119K also attenuated Rac-dependent formation of lamellipodia, a key structure required for metastasis. Constitutively active Rac1 rescued G␤␥ blockade-mediated inhibition of breast cancer cell migration, whereas dominant negative Rac1 inhibited cell migration similar to G␤␥ blockade. Furthermore, M119K suppressed G i protein-coupled CXC chemokine receptor 4 (CXCR4)-dependent MDA-MB-231 cell migration by 80% with an IC 50 value of 1 M, whereas tyrosine kinase receptor-dependent cell migration was significantly less inhibited. However, CXCR4-dependent inhibition of adenylyl cyclase, a G i ␣-mediated response in MDA-MB-231 cells, was not blocked by M119K but was blocked by pertussis toxin, which selectively inactivates G i ␣. This report is the first to directly demonstrate the role of G␤␥ in cancer cell migration and invasion and suggests that targeting G␤␥ signaling pathways may provide a novel strategy for suppressing breast cancer metastasis.Breast cancer is the second largest killer of women by cancer with approximately 40,000 deaths in the United States each year (Jemal et al., 2008). Patients who cannot be cured are primarily those in whom breast cancer has metastasized. Metastasis is a complex pathophysiological process, beginning with the migration and invasion of cancer cells into the surrounding tissues and lymphatics. From these sites, cancer cells can gain access to the circulation and proliferate to form new colonies at metastatic sites in vital organs such as the lung, bone, liver, and brain (StetlerStevenson and Kleiner, 2001). This directed cell migration and invasion is triggered by chemoattractants such as chemokines, growth factors, and matrix metalloproteases, which are sensed by cancer cell surface receptors including integrins, receptor tyrosine kinases, and G protein-coupled receptors (GPCRs). Evidence from preclinical and clinical studies shows excessive activation of GPCRs in breast cancer caused by overexpression of receptors, abnormally elevated ligands for GPCRs, and/or down-regulation of RGS proteins (Dorsam and Gutkind, 2007;Xie et al., 200...

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Gβγ Signaling Promotes Breast Cancer Cell Migration and Invasion

Kirui

Xie

Wolff

et al. 2010

J Pharmacol Exp Ther

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“…In this essay it is pointed out G protein receptors which has an important role in triggering and progressing of cancer can be targeted by imidazopyrazine derivatives. 39 According to results of our study, some of Imidazo[1,2-a]pyrazine derivatives can be used in order to enable telomerase inhibition. In the application of 2n code 6-(4-Metylphenyl-8-(4-chlorophenyl)imidazo[1,2-a]pyrazine (C 19 H 14 N 3 Cl), it was determined that they inhibit telomerase activities at statistically significant degree (Table 2).…”

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confidence: 90%

The effects of some imidazopyrazine derivatives on telomerase inhibition, mtdna damage and mtdna copy number

Mutlu¹,

Bilginer²,

Kayağil³

et al. 2017

actapharm

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“…Twenty five years later and in collaboration with Gespach, IPSEN pharmaceuticals designed pan-inhi�itors of GPCR signaling targeting Ga su�units in the MCF-7 �reast cancer cell line and the invasive growth of epithelial cancer cells and tumors (Ayou� et al, 2009, Prevost et al, 2006 (Fig. 3).…”

Section: When Did You Enter Into the Field Of Cell Signaling?mentioning

confidence: 99%

Signaling networks in cancer - an interview with Christian Gespach

Wever¹

2011

Int. J. Dev. Biol.

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The dynamic, innovative temperament of Christian Gespach is ideally suited to unraveling some aspects of the complex molecular networks connected with signal transduction, cancer progression and treatment. He is one of the pioneers who opened, in the early 1980s, new insights into the signaling mechanisms of G-protein coupled receptor (GPCR) activation, desensitization, internalisation and crosstalks. Twenty five years later and in collaboration with Gespach, IPSEN pharmaceuticals designed pan-inhibitors of GPCR signaling, targeting Ga subunits in breast cancer progression and other epithelial cancers. Creativity is of vital importance to understand signal transduction pathways engaged in cancer cell motility, invasion and drug resistance. Christian Gespach has published more than 200 papers in cancer research, a true signal transduction tale.

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Anticancer Activity of BIM-46174, a New Inhibitor of the Heterotrimeric Gα/Gβγ Protein Complex

Cited by 58 publications

References 44 publications

Gβγ Signaling Promotes Breast Cancer Cell Migration and Invasion

Gβγ Signaling Promotes Breast Cancer Cell Migration and Invasion

The effects of some imidazopyrazine derivatives on telomerase inhibition, mtdna damage and mtdna copy number

Signaling networks in cancer - an interview with Christian Gespach

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