Tyrosine Kinase : Mouse Study Suggests Type 2 Diabetes Potential Treatment

THURSDAY, Dec. 17 (HealthDay News) -- Researchers in Brazil have found that the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor PD153035 improves insulin sensitivity and glucose tolerance in mice fed on a high-fat diet, and may offer a treatment approach for type 2 diabetes, according to a study in the December issue of Diabetes.

Patricia O. Prada, of the State University of Campinas in Brazil, and colleagues put mice on a high-fat diet for eight weeks, then administered PD153035 by tube to the mice for two weeks. They conducted glucose tolerance tests and insulin tolerance tests, as well as tests for biomarkers of inflammation.

The researchers found that treatment with PD153035 for a single day reduced the protein expression of inducible nitric oxide synthase, tumor necrosis factor (TNF)-α, and interleukin (IL)-6, pointing to a reduction of the proinflammatory state in the adipose tissue macrophages. With two weeks of continued treatment, the mice exhibited a marked improvement in glucose tolerance, as well as improved insulin signaling and reduced insulin resistance.


What is PD153035?
PD153035 is reported to be a specific and potent inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase and, to a lesser degree, of the closely related HER2/neu receptor. We show that PD153035 inhibits EGF-dependent EGF receptor phosphorylation and suppresses the proliferation and clonogenicity of a wide panel of EGF receptor-overexpressing human cancer cell lines.

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein. Tyrosine kinases are a subgroup of the larger class of protein kinases. Phosphorylation of proteins by kinases is an important mechanism in signal transduction for regulation of enzyme activity.

EGF receptor autophosphorylation in response to exogenous EGF was completely inhibited at PD153035 concentrations of >75 nM in cells overexpressing the EGF receptor. In contrast, PD153035 only reduced heregulin-dependent tyrosine phosphorylation in HER2/neu-overexpressing cell lines at significantly higher concentrations (1400-2800 nM). PD153035 exposure did not affect the expression of either EGF receptors or HER2/neu.

PD153035 caused a dose-dependent growth inhibition of EGF receptor-overexpressing cell lines at low micromolar concentrations, and the IC50 in monolayer cultures was less than 1 microM in most cell lines tested. At doses of up to 2.5 microM, the IC50 for HER2/neu-overexpressing cells was not reached. In colony-forming assays, the PD153035 growth-inhibitory activity in cultures driven by endogenous (autocrine) ligand was correlated with EGF receptor number, with higher activity in cells expressing higher numbers of EGF receptors and only minimal activity in cells expressing normal numbers of EGF receptors but high HER2/neu levels.

PD153053 also abolished all growth effects mediated by the addition of exogenous EGF; this condition could be reversed upon removal of the compound. Cotreatment with C225, an anti-EGF receptor-blocking monoclonal antibody, further enhanced the antitumor activity of PD153035, suggesting mechanisms of action for C225 other than competition with ligand binding. This latter finding also suggests that combined anti-EGF receptor strategies may be of enhanced benefit against tumors with high levels of EGF receptor expression.