Aims and scopes: 

Imatinib Mesylate, a novel tyrosine kinase inhibitor, has recently been shown to be efficacious in preclinical trials for glioblastoma. It is an ATP analogue, potently and selectively inhibits several protein tyrosine kinase receptors for PDGF, including bcr-abl, and c-kit by interacting with their ATP-binding site. ATP dependent K channels (K-ATP) have important roles in cell metabolism, survival. Glibenclamide, an antidiabetic agent, has been shown to effect drug resistance site SUR subgroups and specific K-ATP channel blocker. Despite these results, the potential modulatory effect of glibenclamide or combined efficacy of imanitib against brain tumours have not been evaluated experimentally. In this study we investigated whether glibenclamide has a synergistic or an antagonistic effect on imatinib-induced cytotoxicity.

Material-method: 

The T98G human glioma chemoresistant experimental brain tumour cell line, that is notoriously difficult to treat with combination chemotherapy, was used in monolayer cultures. We treated T98G glioma cells with a combination of glibenclamide and imatinib at a concentration of 100 and 10 mM respectively at 24^th and 72^th h. Following treatment, we evaluated cell proliferation (MTT), apoptosis (caspase-3 activity), midkine (ELISA) and multidrug resistance protein-MRP (western blot) levels.

Results: 

Glibenclamide and imatinib induced apoptosis and cytotoxicity in gliablastoma cells. Combined usage of two drug has synergic effect on cytotoxicity. Glibenclamide decreased drug resistance protein levels at 24 and 72^th h whereas gliablastoma cells develop resistance to imatinib at 72^th h. Both drugs have decreasing effect on midkine levels which is a hypoxia induced growth factor; takes part in cell proliferation, migration, angiogenesis and inflammation.

Conclusions: 

Our data shows that a combination of imatinib and glibenclamide resulted in enhanced in vitro antitumour activity against human T98G glioma cells in monolayer cultures. Although imatinib's antiproliferative effect has been shown in several cancer cell lines, including human myelogenous leukemia, breast tumor, and melanoma, this is the first study to report glibenclamide's inhibitory effects against a glioma cell line, as well as demonstrate anti-glioma synergy with imatinib and its ability to induce apoptosis. Glibenclamide might be a potent chemotherapic agent to reverse multidrug resistance to cancer chemotherapy in several tumor cell lines in vitro.

This study was supported by TUBITAK project no SBAG-108S248.