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.

Ulcerative colitis (UC) is a major form of inflammatory bowel disease (IBD) with high incidence and prevalence in many countries. Patients with UC usually suffer from a lifetime of debilitating physical symptoms. Therefore, developing effective therapeutic strategy that can manage this disease better and improve patients’ life quality is in urgent need. Sesamin (SSM) is a lignan derived from sesame seeds. In this study, the protective effect of SSM against UC and the underlying mechanism were investigated in vitro and in vivo. Our data showed that SSM protected Caco-2 cells from H₂O₂-induced oxidative stress injury via GSH-mediated scavenging of reactive oxygen species (ROS). Dual luciferase reporter assay showed that the transcriptional activity of nuclear factor erythroid-related factor 2 (Nrf2) was significantly increased by SSM, and the ability of SSM to activate Nrf2-targeted genes was further confirmed in Caco-2 cells using western blot and quantitative real-time PCR (qRT-PCR). In contrast, Nrf2 knockdown abolished the protective effect of SSM. Additionally, we found that SSM also activated advanced protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) in Caco-2 cells, while either AKT or ERK inhibition can prevent SSM-mediated nuclear translocation of Nrf2. Furthermore, SSM displayed a better protective effect against dextran sulfate sodium- (DSS-) induced UC compared with 5-aminosalicylic acid (5-ASA) in C57BL/6 mice. The enhanced Nrf2 signaling and activated AKT/ERK were also observed in the colon of mice after SSM administration. These results first demonstrate the protective effect of SSM against UC and indicate that the effect is associated with AKT/ERK activation and subsequent Nrf2 signaling enhancement. This study provides a new insight into the medicinal value of SSM and proposes it as a new natural nutrition for better managing the symptoms of UC.

Triptolide, the major active component of Tripterygium wilfordii Hook f. (TWHF), has a wide range of pharmacological activities. However, the toxicities of triptolide, particularly the hepatotoxicity, limit its clinical application. The hepatotoxicity of triptolide has not been well characterized yet. The aim of this study was to investigate the role of NF-E2-related factor 2 (Nrf2) in triptolide-induced toxicity and whether activation of Nrf2 could protect against triptolide-induced hepatotoxicity. The results showed that triptolide caused oxidative stress and cell damage in HepG2 cells, and these toxic effects could be aggravated by Nrf2 knockdown or be counteracted by overexpression of Nrf2. Treatment with a typical Nrf2 agonist, sulforaphane (SFN), attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. Moreover, the hepatoprotective effect of SFN on triptolide-induced liver injury was associated with the activation of Nrf2 and its downstream targets. Collectively, these results indicate that Nrf2 activation protects against triptolide-induced hepatotoxicity.

The pentose phosphate pathway (PPP), which branches from glycolysis, is correlated with cancer cell proliferation, survival and senescence. In this study, differences in the metabolic profile of the PPP and the redox status of human lung carcinoma A549 cells and cisplatin-induced multidrug-resistant A549/DDP cells were analyzed and evaluated. The results showed that A549/DDP cells exhibited differential PPP-derived metabolic features and redox-related molecules. A549/DDP cells exhibited increased expression and enzymatic activity of PPP enzyme glucose-6-phosphate dehydrogenase (G6PD). Furthermore, as demonstrated by the apoptotic rate, cell viability, and colony formation, inhibition of G6PD by siRNA or an inhibitor sensitized A549/DDP cells to cisplatin. Additionally, inhibition of G6PD restored the cisplatin sensitivity of A549/DDP cells by influencing redox homeostasis. In conclusion, overcoming cisplatin resistance through inhibition of G6PD could improve the understanding of the mechanisms underlying cisplatin-induced resistance in human lung cancer and may provide insights into the therapeutic potential of this treatment to combat resistance.