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

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 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.

Luteolin, a Bioflavonoid Inhibits Colorectal Cancer through Modulation of Multiple Signaling Pathways: A Review

“…Luteolin is reported to activate the Nrf2 in AOM-induced colon cancer (Pandurangan et al, 2014a). On the other hand luteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the nrf2 pathway (Chian et al, 2014). This phenomenon was further confirmed by the elevated expression of GST-α and GST-µ (Summart et al, 2014).…”

Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells

“…Luteolin, also known as 3',4',5',7'-tetrahydroxyflavone, is a flavonoid compound that has a C6-C3-C6 structure and possesses two benzene rings, an oxygen-containing ring and a 2-3 carbon double bond. This compound has been Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells LAN found to possess various beneficial properties, including antioxidant (11), anti-inflammatory (12), anti-bacterial (13) and anti-cancer activities (14)(15)(16)(17). Recently, Reipas et al (18) reported that luteolin is a novel p90 RSK inhibitor that can be considered as a promising candidate agent for the treatment of liver, lung, breast, colon, prostate, gastric and ovarian cancer, as well as melanoma.…”

Luteolin-loaded Phytosomes Sensitize Human Breast Carcinoma MDA-MB 231 Cells to Doxorubicin by Suppressing Nrf2 Mediated Signalling

“…Many studies have showed that luteolin play an important role in prevention of the human body against inflammation, reactive oxygen species and cancer. Luteolin can inhibit Nrf2 signaling activation in drug-resistant cells and suppress expression of Nrf2-targeted genes in small intestinal cells of wild type mice, but had no significant effects in knockout mice (Chian et al, 2014). Furthermore, luteolin decreased activity of mitochondrial enzyme significantly in mice with colon cancer induced with Azoxymethane (Pandurangan et al, 2012).…”