Nrf2 Overexpression Predicts Prognosis and 5-FU Resistance in Gastric Cancer

Hu, Xiufeng; Yao, Jun; Gao, Shegan; Wang, Xinshuai; Peng, Xiu‐Qing; Yang, Yuxin; Feng, Xiaojun

doi:10.7314/apjcp.2013.14.9.5231

Cited by 73 publications

(49 citation statements)

References 19 publications

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“…High expression of NRF2 in tumor issues predicted much lower survival rate compared to NRF2-negative patients receiving 100-month 5-FU chemotherapy. The similar results were also acquired from Chinese patients with GC (Hu et al, 2013). 55.9% of reported Chinese specimens showed high expression for NRF2 with lower overall response rate and disease-free rate under 5-FU treatment.…”

Section: Gastric Cancersupporting

confidence: 86%

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

Bai

Chen

Hou

et al. 2016

Drug Metabolism Reviews

129

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Chemoresistance is a disturbing barrier in cancer therapy, which always results in limited therapeutic options and unfavorable prognosis. Nuclear factor E2-related factor 2 (NRF2) controls the expression of genes encoding cytoprotective enzymes and transporters that protect against oxidative stress and electrophilic injury to maintain intrinsic redox homeostasis. However, recent studies have demonstrated that aberrant activation of NRF2 due to genetic and/or epigenetic mutations in tumor contributes to the high expression of phase I and phase II drug-metabolizing enzymes, phase III transporters, and other cytoprotective proteins, which leads to the decreased therapeutic efficacy of anticancer drugs through biotransformation or extrusion during chemotherapy. Therefore, a better understanding of the role of NRF2 in regulation of these enzymes and transporters in tumors is necessary to find new strategies that improve chemotherapeutic efficacy. In this review, we summarized the recent findings about the chemoresistance-promoting role of NRF2, NRF2-regulated phase I and phase II drug-metabolizing enzymes, phase III drug efflux transporters, and other cytoprotective genes. Most importantly, the potential of NRF2 was proposed to counteract drug resistance in cancer treatment.

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Section: Gastric Cancersupporting

confidence: 86%

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

Bai

Chen

Hou

et al. 2016

Drug Metabolism Reviews

129

View full text Add to dashboard Cite

show abstract

“…Doxorubicin resistance in an ovarian carcinoma cell line (A2780DR) was accompanied by an elevation in Nrf2 activity, which restored sensitivity to doxorubicin after stable transfection of A2780DR cells with Nrf2-shRNA (Shim et al, 2009). Nrf2 also confers resistance to chemotherapeutic drug 5-FU in gastric cancer cells (Hu et al, 2013). Therefore, Nrf2 is a potential target for reversing tumor resistance (Jeong et al, 2006;Kwak and Kensler, 2010;Pandurangan and Esa, 2013).…”

Section: Introductionmentioning

confidence: 99%

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

Chian

Li²,

Wang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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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.

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“…Nrf2 plays dual roles in cancer, but more emerging data had shown it performs its role as a protooncogene.Studies was shown overexpression of Nrf2in the gastric cancer samples and gastric cancer cell lines (Hu et al, 2013) Luteolin (2-(3, 4-Dihydroxyphenyl) -5, 7-dihydroxy-4-chromenone) is one of the most common flavonoid that is found in celery, green pepper, honey, proposes and chamomile tea. Many studies have showed that luteolin play an important role in prevention of the human body against inflammation, reactive oxygen species and cancer.…”

Section: Discussionmentioning

confidence: 99%

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

Sabzichi

Hamishehkar²,

Ramezani³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Nuclear factor erythroid 2-related factor 2 (Nrf2) has been recognized as a transcription factor that controls mechanisms of cellular defense response by regulation of three classes of genes, including endogenous antioxidants, phase II detoxifying enzymes and transporters. Previous studies have revealed roles of Nrf2 in resistance to chemotherapeutic agents and high level expression of Nrf2 has been found in many types of cancer. At physiological concentrations, luteolin as a flavonoid compound can inhibit Nrf2 and sensitize cancer cells to chemotherapeutic agents. We reported luteolin loaded in phytosomes as an advanced nanoparticle carrier sensitized MDA-MB 231 cells to doxorubicin. In this study, we prepared nano phytosomes of luteolin to enhance the bioavailability of luteolin and improve passive targeting in breast cancer cells. Our results showed that cotreatment of cells with nano particles containing luteolin and doxorubicin resulted in the highest percentage cell death in MDA-MB 231cells (p<0.05). Furthermore, luteolin-loaded nanoparticles reduced Nrf2 gene expression at the mRNA level in cells to a greater extent than luteolin alone (p<0.05). Similarly, expression of downstream genes for Nrf2 including Ho1 and MDR1 were reduced significantly (p<0.05). Inhibition of Nrf-2 expression caused a marked increase in cancer cell death (p<0.05). Taken together, these results suggest that phytosome technology can improve the efficacy of chemotherapy by overcoming resistance and enhancing permeability of cancer cells to chemical agents and may thus be considered as a potential delivery system to improve therapeutic protocols for cancer patients.

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Nrf2 Overexpression Predicts Prognosis and 5-FU Resistance in Gastric Cancer

Cited by 73 publications

References 19 publications

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

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

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

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