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Molecular Pharmacology

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Research ArticleArticle

αvβ3 Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species

Anamaria Brozović, Dragomira Majhen, Vibor Roje, Nevenka Mikac, Sanjica Jakopec, Gerhard Fritz, Maja Osmak and Andreja Ambriović-Ristov
Molecular Pharmacology July 2008, 74 (1) 298-306; DOI: https://doi.org/10.1124/mol.107.043836
Anamaria Brozović
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Dragomira Majhen
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Vibor Roje
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Nevenka Mikac
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Sanjica Jakopec
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Gerhard Fritz
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Maja Osmak
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Andreja Ambriović-Ristov
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Abstract

As a model for determination of the role of integrins in drug resistance, we used αvβ3 integrin-negative human laryngeal carcinoma cell line (HEp2) and three HEp2-derived cell clones with a gradual increase of αvβ3 integrin expression. The αvβ3 integrin expression protects cells from cisplatin, mitomycin C, and doxorubicin. In HEp2-αvβ3 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-αvβ3 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-αvβ3 integrin-expressing cells, indicating that Bcl-2 is not involved in resistance mechanism. There was no difference in DNA platination between HEp2 and HEp2-αvβ3 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-αvβ3 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 αvβ3-expressing cells to eliminate drug-induced ROS.

Footnotes

  • This work was funded by grants 098-0982913-2748 and 098-0982913-2850 from The Ministry of Science, Education and Sport of the republic of Croatia.

  • ABBREVIATIONS: GSH, glutathione; BSO, buthionine sulfoximine; HEp2, human laryngeal carcinoma cells; ROS, reactive oxidative species; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBS, phosphate-buffered saline; ERK, extracellular signal-regulated kinase; siRNA, small interfering RNA; NAC, N-acetyl-l-cysteine; Ad5, adenovirus type 5; cDDP, cisplatin; DOX, doxorubicin.

    • Received November 26, 2007.
    • Accepted April 25, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (1)
Molecular Pharmacology
Vol. 74, Issue 1
1 Jul 2008
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Research ArticleArticle

αvβ3 Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species

Anamaria Brozović, Dragomira Majhen, Vibor Roje, Nevenka Mikac, Sanjica Jakopec, Gerhard Fritz, Maja Osmak and Andreja Ambriović-Ristov
Molecular Pharmacology July 1, 2008, 74 (1) 298-306; DOI: https://doi.org/10.1124/mol.107.043836

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Research ArticleArticle

αvβ3 Integrin-Mediated Drug Resistance in Human Laryngeal Carcinoma Cells Is Caused by Glutathione-Dependent Elimination of Drug-Induced Reactive Oxidative Species

Anamaria Brozović, Dragomira Majhen, Vibor Roje, Nevenka Mikac, Sanjica Jakopec, Gerhard Fritz, Maja Osmak and Andreja Ambriović-Ristov
Molecular Pharmacology July 1, 2008, 74 (1) 298-306; DOI: https://doi.org/10.1124/mol.107.043836
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