Molecular pharmacology
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Molecular pharmacology · Jul 2008
alpha(v)beta(3) Integrin-mediated drug resistance in human laryngeal carcinoma cells is caused by glutathione-dependent elimination of drug-induced reactive oxidative species.
As a model for determination of the role of integrins in drug resistance, we used alpha(v)beta(3) integrin-negative human laryngeal carcinoma cell line (HEp2) and three HEp2-derived cell clones with a gradual increase of alpha(v)beta(3) integrin expression. The alpha(v)beta(3) integrin expression protects cells from cisplatin, mitomycin C, and doxorubicin. In HEp2-alpha(v)beta(3) integrin-expressing cells, the constitutive expression of Bcl-2 protein and the level of glutathione (GSH) were increased compared with HEp2 cells. ⋯ There was no difference in DNA platination between HEp2 and HEp2-alpha(v)beta(3) integrin-expressing cells, indicating that the mechanism of drug resistance is independent of cisplatin detoxification by GSH. A strong increase of reactive oxidative species (ROS) formation during cisplatin or doxorubicin treatment in HEp2 cells was reduced in HEp2-alpha(v)beta(3) integrin-expressing cells. Since this increased elimination of ROS could be reverted by GSH depletion, we concluded that multidrug resistance is the consequence of GSH-dependent increased ability of alpha(v)beta(3)-expressing cells to eliminate drug-induced ROS.