Dobesilate diminishes activation of the mitogen ‐ activated protein kinase ERK1/2 in glioma cells

Abstract

Fibroblast growth factors (FGFs) and their receptors, regularly expressed at high levels in gliomas, are further upregulated during the transition of the tumor from low- to high-grade malignancy, and are essential for glioma progression. FGFs induce upregulation of the mitogen-activated protein kinase (MAPK) signaling cascade in cultured glioma cells, which suggests that MAPK pathway participates in the FGF-dependent glioma development. Recently, it has been shown that dobesilate, an inhibitor of FGF mitogenic activity, shows antiproliferative and proapoptotic activities in glioma cell cultures. Accordingly, it should be expected this new synthetic FGF inhibitor to affect the activation levels of MAPK. Here we report that immunocytochemical and Western blot data unequivocally show that treatment of cell cultures with dobesilate causes a significant decrease of the intracellular levels of ERK1/2 activation, one of the components of the MAPK signalling cascade. This finding supports an important role for dobesilate in glioma growth, suggesting that dobesilate should be a treatment to be born in mind for glioma management.

Signal transducer and activator of transcription 1 (Stat1) maintains basal mRNA expression of pro-survival stat3-target genes in glioma C6 cells

“…These results appear contradictory to our results suggesting that Stat1, and not Stat3, maintains the expression of Bcl2l1 in the C6 glioma cells. However, dobesilate also inhibits ERK1/2 pathway [Cuevas et al, 2006a]. Therefore, the reduction in P-Stat3 level may be not causative of the downregulation of Bcl2l1 and Ccnd1.…”

Synergistic Inhibition of Survival, Proliferation, and Migration of U87 Cells with a Combination of LY341495 and Iressa

“…The synergistic effect of Iressa and LY341495 may be due to the inhibition of converging and overlapping pathways such as Akt-1 and MAP kinase pathways. These two pathways have been shown to be utilized both by EGFR and mGluR upon activation by glutamate [9], [39], [41], [42].…”

“…Our data suggests that a more positive feedback loop exist between mGluR and EGFR activation in U87 cells, because a combination of inhibition of mGluR and EGFR is more effective than combination of inhibition AMPA receptor and EGFR inhibition. The synergism exhibited by Iressa and LY341495 may stem from the fact that they inhibit activation of Akt-1 and ERK1/2 activation via the inhibition of EGFR and mGluR activation [9], [39], [41]. Depending on the pathways activated in different gliomas, the combination of inhibitors that block growth proliferation and induce apoptosis may be different.…”

“…MAP kinase pathways regulate proliferation, differentiation and survival of cells in several types of tumors including glioma [40]. ERK1 and 2 are members of the MAP kinase pathway that are regulated by phosphorylation, and have been targeted by drugs to reduce proliferation in glioma [41].…”

“…Besides the activation of the glutamate receptors such as AMPA receptor, mGluR and EGFR, Akt activation is involved in the stimulation of growth by more than one pathway (AMPA receptor and EGFR receptor and mGluR activation). Furthermore, the MAP kinase pathway is activated via both EGFR and mGluR activation [9], [41], [42]. An effective treatment may necessitate the use of more than one drug for a more vehement inhibition of growth.…”