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_vβ₃ Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species

Anamaria Brozovi, Dragomira Majhen, Vibor Roje, Nevenka Mikac, Sanjica Jakopec, Gerhard Fritz, Maja Osmak, and Andreja Ambriovi-Ristov

Divisions of Molecular Biology (A.B., D.M., S.J., M.O., A.A.R.) and Marine and Environmental Research (V.R., N.M.), Ruðer Boskovi Institute, Zagreb, Croatia; and Department of Toxicology, University Mainz, Mainz, Germany (G.F.)

As a model for determination of the role of integrins in drug resistance, we used _vβ₃ integrin-negative human laryngeal carcinoma cell line (HEp2) and three HEp2-derived cell clones with a gradual increase of _vβ₃ integrin expression. The _vβ₃ integrin expression protects cells from cisplatin, mitomycin C, and doxorubicin. In HEp2-_vβ₃ integrin-expressing cells, the constitutive expression of Bcl-2 protein and the level of glutathione (GSH) were increased compared with HEp2 cells. Pretreatment of HEp2-_vβ₃ integrin-expressing cells with an inhibitor of GSH synthesis, buthionine sulfoximine (BSO), decreased the level of GSH and partially reverted drug resistance to all above-mentioned drugs, but it did not influence the expression of Bcl-2. Sensitivity to selected anticancer drugs did not change with overexpression of Bcl-2 in HEp2 cells, nor with silencing of Bcl-2 in HEp2-_vβ₃ integrin-expressing cells, indicating that Bcl-2 is not involved in resistance mechanism. There was no difference in DNA platination between HEp2 and HEp2-_vβ₃ 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-_vβ₃ 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 _vβ₃-expressing cells to eliminate drug-induced ROS.

Address correspondence to: Dr. Andreja Ambriovi-Ristov, Laboratory for Genotoxic Agents, Division of Molecular Biology, Ru[dcrossed]er Boskovi Institute, Bijenika 54, 10000 Zagreb, Croatia. E-mail: andrea{at}irb.hr