αvβ3 integrin-mediated drug resistance in human laryngeal carcinoma cells is caused by glutathione-dependent elimination of drug-induced reactive oxidative species

被引：37

作者：

Brozovic, Anamaria

Majhen, Dragomira

Roje, Vibor ^{[2
]}

Mikac, Nevenka ^{[2
]}

Jakopec, Sanjica

Fritz, Gerhard ^{[3
]}

Osmak, Maja

Ambriovic-Ristov, Andreja ^{[1
]}

机构：

[1] Rudjer Boskovic Inst, Div Mol Biol, Lab Genotox Agents, Zagreb 10000, Croatia

[2] Rudjer Boskovic Inst, Div Marine & Environm Res, Zagreb 10000, Croatia

[3] Johannes Gutenberg Univ Mainz, Dept Toxicol, Mainz, Germany

来源：

MOLECULAR PHARMACOLOGY | 2008年 / 74卷 / 01期

关键词：

D O I：

10.1124/mol.107.043836

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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. Pretreatment of HEp2-alpha(v)beta(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-alpha(v)beta(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-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.

引用

页码：298 / 306

页数：9

共 39 条

[1] Increased adenoviral transduction efficacy in human laryngeal carcinoma cells resistant to cisplatin is associated with increased expression of integrin αvβ3 and coxsackie adenovirus receptor [J].