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http://dx.doi.org/10.7314/APJCP.2014.15.6.2911

Luteolin Sensitizes Two Oxaliplatin-Resistant Colorectal Cancer Cell Lines to Chemotherapeutic Drugs Via Inhibition of the Nrf2 Pathway  

Chian, Song (Department of Biochemistry and Genetics, School of Medicine, Zhejiang University)
Li, Yin-Yan (Department of Pharmacology, School of Medicine, Zhejiang University)
Wang, Xiu-Jun (Department of Pharmacology, School of Medicine, Zhejiang University)
Tang, Xiu-Wen (Department of Biochemistry and Genetics, School of Medicine, Zhejiang University)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.15, no.6, 2014 , pp. 2911-2916 More about this Journal
Abstract
Oxaliplatin is a first-line therapy for colorectal cancer, but cancer cell resistance to the drug compromises its efficacy. To explore mechanisms of drug resistance, we treated colorectal cancer cells (HCT116 and SW620) long-term with oxaliplatin and established stable oxaliplatin-resistant lines (HCT116-OX and SW620-OX). Compared with parental cell lines, $IC_{50}$s for various chemotherapeutic agents (oxaliplatin, cisplatin and doxorubicin) were increased in oxaliplatin-resistant cell lines and this was accompanied by activation of nuclear factor erythroid-2 p45-related factor 2 (Nrf2) and NADPH quinone oxidoreductase 1 (NQO1). Furthermore, luteolin inhibited the Nrf2 pathway in oxaliplatin-resistant cell lines in a dose-dependent manner. Luteolin also inhibited Nrf2 target gene [NQO1, heme oxygenase-1 (HO-1) and $GST{\alpha}1/2$] expression and decreased reduced glutathione in wild type mouse small intestinal cells. There was no apparent effect in Nrf2-/- mice. Luteolin combined with other chemotherapeutics had greater anti-cancer activity in resistant cell lines (combined index values below 1), indicating a synergistic effect. Therefore, adaptive activation of Nrf2 may contribute to the development of acquired drug-resistance and luteolin could restore sensitivity of oxaliplatin-resistant cell lines to chemotherapeutic drugs. Inhibition of the Nrf2 pathway may be the mechanism for this restored therapeutic response.
Keywords
Luteolin; colorectal cancer; oxaliplatin-resistant cell lines; Nrf2; sensitization;
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