Nrf2 overexpression is associated with P-glycoprotein upregulation in gastric cancer

Jeddi, Farhad; Soozangar, Narges; Sadeghi, Mohammad Reza; Somi, Mohammad Hossein; Shirmohamadi, Masoud; Eftekharsadat, Amirtaher; Samadi, Nasser

doi:10.1016/j.biopha.2017.10.129

Cited by 66 publications

(34 citation statements)

References 43 publications

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“…The transcriptional regulation of the MDR1 gene is highly complex. The nuclear receptor PXR and the transcription factor Nrf2 play important roles in elevating MDR1 gene transcription and ultimately increasing P-gp function (Chen et al, 2012;Jeddi et al, 2018). Additionally, dysregulation of PXR/Nrf2 activity in the intestine is thought to contribute to colitis pathophysiology (Khor et al, 2006;Yang et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Berberine Upregulates P-Glycoprotein in Human Caco-2 Cells and in an Experimental Model of Colitis in the Rat via Activation of Nrf2-Dependent Mechanisms

Jing

Safarpour

Zhang

et al. 2018

J Pharmacol Exp Ther

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Downregulation of P-glycoprotein (P-gp) is implicated in the pathophysiology of inflammatory bowel disease (IBD). Berberine, a principal isoquinoline alkaloid extracted from species, has been reported to exhibit therapeutic potential in IBD. In this study, we used a dextran sulfate sodium (DSS)-induced colitis rat model to evaluate the effect of berberine on P-gp and explore its mechanism of action. Berberine treatment improved DSS-induced colitis symptoms, attenuated inflammatory markers (myeloperoxidase, tumor necrosis factor-, and interleukin-1 and -6), and enhanced P-gp expression in a dose-dependent manner. Although colonic expression of the P-gp-related nuclear receptor pregnane X receptor and transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) were downregulated in the colitis model, gene and protein expression analysis revealed that berberine treatment reversed only the downregulation of Nrf2. In vitro studies using Caco-2 cells showed that the multidrug resistance 1 () gene and P-gp protein were upregulated by berberine in a dose- and time-dependent manner. Significant upregulation of the gene by berberine was abrogated by Nrf2 silencing, indicating that the Nrf2-mediated pathway was responsible for this activation. Luciferase assays showed a dose-dependent increase in Nrf2 reporter gene activity after berberine treatment in Caco-2 cells, with a significant 2-fold elevation at 2.5M berberine, suggesting that berberine is a strong Nrf2 activator. These results indicate the possible involvement of Nrf2-mediated upregulation of P-gp in the therapeutic effect of berberine on colitis and highlight the potential of P-gp and/or Nrf2 as new therapeutic targets for IBD.

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Section: Discussionmentioning

confidence: 99%

Berberine Upregulates P-Glycoprotein in Human Caco-2 Cells and in an Experimental Model of Colitis in the Rat via Activation of Nrf2-Dependent Mechanisms

Jing

Safarpour

Zhang

et al. 2018

J Pharmacol Exp Ther

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“…Mediates the Na+-independent uptake of organic anions 38 P-gp P-glycoprotein an ATP-dependent efflux pump of wide range of xenobiotics 39 Fatty acid synthesis and oxidation Under the physiological condition, Nrf2 maintains the cellular redox homeostasis and exerts anti-inflammatory functions and further anticancer activities, hence supports cell survival.…”

Section: Oatp2 Organic Anion-transporting Polypeptidementioning

confidence: 99%

Nrf2 in cancers: A double‐edged sword

2019

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The Nrf2/Keap1 pathway is an important signaling cascade responsible for the resistance of oxidative damage induced by exogenous chemicals. It maintains the redox homeostasis, exerts anti‐inflammation and anticancer activity by regulating its multiple downstream cytoprotective genes, thereby plays a vital role in cell survival. Interestingly, in recent years, accumulating evidence suggests that Nrf2 has a contradictory role in cancers. Aberrant activation of Nrf2 is associated with poor prognosis. The constitutive activation of Nrf2 in various cancers induces pro‐survival genes and promotes cancer cell proliferation by metabolic reprogramming, repression of cancer cell apoptosis, and enhancement of self‐renewal capacity of cancer stem cells. More importantly, Nrf2 is proved to contribute to the chemoresistance and radioresistance of cancer cells as well as inflammation‐induced carcinogenesis. A number of Nrf2 inhibitors discovered for cancer treatment were reviewed in this report. These provide a new strategy that targeting Nrf2 could be a promising therapeutic approach against cancer. This review aims to summarize the dual effects of Nrf2 in cancer, revealing its function both in cancer prevention and inhibition, to further discover novel anticancer treatment.

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“…Tazehkand, Akbarzadeh, Velaie, Sadeghi, and Samadi, (2018) have demonstrated that inhibition of the Nrf2 pathway in CRC cells with high rates of Her2 overexpression could have a high impact to restore oxaliplatin‐induced apoptosis in these cells. Nrf2 downregulation could also improve the stage and grade of the disease followed by downregulation of P‐glycoprotein expression (Jeddi et al, 2018). Given these results, the inhibition of Nrf2/ABCB1 signaling could be contemplated as a novel approach to elevate the effects of chemotherapeutic drugs in CRC patients (Sadeghi et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

PD‐1/PD‐L1‐dependent immune response in colorectal cancer

Payandeh

Khalili

Somi

et al. 2020

Journal Cellular Physiology

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110

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Colorectal cancer (CRC) is still considered as the third most frequent cancer in the world. Microsatellite instability (MSI), inflammation, and microRNAs have been demonstrated as the main contributing factors in CRC. Subtype 1 CRC is defined by NK cells infiltration, induction of Th1 lymphocyte and cytotoxic T cell responses as well as upregulation of immune checkpoint proteins including programmed cell death‐1 (PD‐1). Based on the diverse features of CRC, such as the stage and localization of the tumor, several treatment approaches are available. However, the efficiency of these treatments may be decreased due to the development of diverse resistance mechanisms. It has been proven that monoclonal antibodies (mAbs) can increase the effectiveness of CRC treatments. Nowadays, several mAbs including nivolumab and pembrolizumab have been approved for the treatment of CRC. Immune checkpoint receptors including PD‐1 can be inhibited by these antibodies. Combination therapy gives an opportunity for advanced treatment for CRC patients. In this review, an update has been provided on the molecular mechanisms involved in MSI colorectal cancer immune microenvironment by focusing on PD‐ligand 1 (PD‐L1) and treatment of patients with advanced immunotherapy, which were examined in the different clinical trial phases. Considering induced expression of PD‐L1 by conventional chemotherapeutics, we have summarized the role of PD‐L1 in CRC, the chemotherapy effects on the PD‐1/PD‐L1 axis and novel combined approaches to enhance immunotherapy of CRC by focusing on PD‐L1.

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Nrf2 overexpression is associated with P-glycoprotein upregulation in gastric cancer

Cited by 66 publications

References 43 publications

Berberine Upregulates P-Glycoprotein in Human Caco-2 Cells and in an Experimental Model of Colitis in the Rat via Activation of Nrf2-Dependent Mechanisms

Berberine Upregulates P-Glycoprotein in Human Caco-2 Cells and in an Experimental Model of Colitis in the Rat via Activation of Nrf2-Dependent Mechanisms

Nrf2 in cancers: A double‐edged sword

PD‐1/PD‐L1‐dependent immune response in colorectal cancer

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