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, IC50s 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 GSTα1/2] 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.
Highlights
Oxaliplatin is a third generation platinum chemotherapeutic which binds to DNA to form platinumDNA adducts that inhibit DNA synthesis and repair to confer cytotoxicity and anti-tumor activity
Multidrug resistance-related protein (MRP) activation may occur such that cancer drugs are transported out of tumor cells, decreasing therapeutic concentrations and efficacy (Conseil et al, 2005)
AKR1C was reported to be elevated in an oxaliplatinresistant human gastric carcinoma cell line, and knockout of nuclear factor erythroid-2 p45-related factor 2 (Nrf2) can decrease AKR1C expression and reverse drug-resistance to oxaliplatin in S3 cells (Chen et al, 2013)
Summary
Oxaliplatin is a third generation platinum chemotherapeutic which binds to DNA to form platinumDNA adducts that inhibit DNA synthesis and repair to confer cytotoxicity and anti-tumor activity. Investigating mechanisms of tumor cell oxaliplatin resistance may offer data to reverse this reduced efficacy and provide promising targets for new clinical trials. Nrf is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1) whereby Keap maintains Nrf at low concentrations in the cytoplasm (Itoh et al, 2010; Magesh, et al, 2012). Dysfunction of this pathway leads to constitutive activation of Nrf and chemoresistance in many cancer cells types (DeNicola et al, 2011; Konstantinopoulos et al, 2011; Niture and Jaiswal, 2012). Nrf is a potential target for reversing tumor resistance (Jeong et al, 2006; Kwak and Kensler, 2010; Pandurangan and Esa, 2013)
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