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Dragun, Zrinka; Roje, Vibor; Mikac, Nevenka; Raspor, Biserka. Preliminary assessment of total dissolved trace metal concentrations in Sava River water. // Environmental Monitoring and Assessment. 159 (2009)

As a model for determination of the role of integrins in drug resistance, we used ␣ v ␤ 3 integrin-negative human laryngeal carcinoma cell line (HEp2) and three HEp2-derived cell clones with a gradual increase of ␣ v ␤ 3 integrin expression. The ␣ v ␤ 3 integrin expression protects cells from cisplatin, mitomycin C, and doxorubicin. In HEp2-␣ v ␤ 3 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-␣ v ␤ 3 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-␣ v ␤ 3 integrin-expressing cells, indicating that Bcl-2 is not involved in resistance mechanism. There was no difference in DNA platination between HEp2 and HEp2-␣ v ␤ 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-␣ v ␤ 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 ␣ v ␤ 3 -expressing cells to eliminate drug-induced ROS.Chemotherapy often results in the development of drug resistance. Several molecular mechanisms have been recognized as a cause of resistance, such as reduced drug accumulation, increased drug inactivation, increased ability to repair and/or tolerate DNA lesions, and inhibition of apoptosis. Recent findings show that integrin-mediated adhesion to the extracellular matrix can modify cellular response to chemotherapeutic drugs through mechanisms such as inhibition of apoptosis, decreased cellular proliferation, and alterations in a drug target (Damiano, 2002;Ambriović-Ristov and Osmak, 2006). Integrins are cell surface adhesion molecules that connect cells to components of the extracellular matrix. They are assembled from a set of diverse ␣-(18) and ␤-(8) subunits that associate to form 24 differentially composed heterodimers exhibiting specific but also redundant ligand binding and expression patterns. Integrins modulate many signaling pathways, supporting cell survival and proliferation and influencing expression of differentiation-regulated genes (Danen, 2005).The most extensively used model for investigation of molecular mechanisms of drug resistance is the development of resistant cells by selected anticancer drug treatment and then comparing the biological and biochemical characteristics of those cells, allowing for the causes of drug resistance to be determined. Despite increased expression of several integrin subunits and/or he...

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