Role of NF-E2 related factor 2 (Nrf2) on chemotherapy resistance in acute myeloid leukemia (AML) and the effect of pharmacological inhibition of Nrf2

Karathedath, Sreeja; Rajamani, Bharathi M; Aalam, Syed Mohammed Musheer; Abraham, Ajay; Varatharajan, Savitha; Krishnamurthy, Partha; Mathews, Vikram; Velayudhan, Shaji R; Balasubramanian, Poonkuzhali

doi:10.1371/journal.pone.0177227

Cited by 68 publications

(46 citation statements)

References 36 publications

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“…Nrf2 inhibition by luteilin in oxaliplatin resistant colon cancer cells strongly had a synergistic effect with different chemotherapy drugs including oxaliplatin, doxorubicin [48] and Nrf2 suppression through Brusatol sensitized resistant acute myeloid leukemia (AML) cells to arsenic trioxide (ATO), daunorubicin (Dnr), and cytarabine (Ara-c) drugs [56]. Knocking down or silencing of Nrf2 reduced phospho-AKT, induced P27, and consequently promoted doxorubicin cytotoxicity and induced apoptosis in SKOV3 ovarian cancer cell line [57,58].…”

Section: Discussionmentioning

confidence: 99%

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The Potential Role of Nrf2-PD-L1 Axis in Promoting of Oxaliplatin Resistance in Colon Cancer Cells

Payandeh¹,

Tazehkand²,

Mansoori³

et al. 2020

Preprint

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Background: Nuclear factor−erythroid 2−related factor 2 (Nrf2) has a key function in promoting chemoresistance in various cancers. PD-L1 is one of the downstream targets of Nrf2 signaling pathway, having some beneficial impacts on tumors growth by inhibition of the immune system. The aim of this study was to investigate the potential role of Nrf2- PD- L1 axis in the promotion of oxaliplatin resistance in colon cancer cells. Result: Our data revealed that Nrf2 and PD-L1 mRNA expressions were markedly higher in tumor tissues compared to margin tissues. PD-L1 mRNA expression level was also increased in the resistant cells. However, Nrf2 expression was decreased and increased in SW480/Res and LS174T/Res cells, respectively. Nrf2 inhibition through siRNA in SW480/Res and LS174T/Res decreased the IC50 values of oxaliplatin. Inhibition of Nrf2 significantly increased oxaliplatin-induced apoptosis and reduced migration in SW480/Res cells when accompanied with oxaliplatin. Conclusion: Our study suggests that effective inhibition of Nrf2/PD-L1 signaling pathways can be considered as a novel approach to improve oxaliplatin efficacy in colon cancer patients.

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Section: Discussionmentioning

confidence: 99%

“…Our results showed that the IC50 values of oxaliplatin in SW480 and LS174T cells increased from 10. 56 (Fig.7).…”

Section: Nrf2 Suppression Caused a Reduction In Cell Survivabilitymentioning

confidence: 97%

The Potential Role of Nrf2-PD-L1 Axis in Promoting of Oxaliplatin Resistance in Colon Cancer Cells

Payandeh¹,

Tazehkand²,

Mansoori³

et al. 2020

Preprint

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“…Also, Karathedath et al, reported that NRF2 overexpression in AML cell lines and primary AML samples caused resistance to Cytarabine, Daunorubicin and Arsenic trioxide (ATO). Importantly, Brusatol was found to markedly decrease the NRF2 content and consequently the expression of its target genes GCLC, GCLM, HMOX-1, and NQO1, promoting ROS accumulation and apoptosis [314]. Finally, in a recent study from Xiang et al, the overactivation of NRF2 signaling was found to mediate Gemcitabine resistance in human PANC-1, PATU-8988 and BXPC3 pancreatic ductal adenocarcinoma cancer (PDAC) cell lines.…”

Section: Natural Compounds That Impair Nrf2 Signaling By Interfering mentioning

confidence: 94%

Potential Applications of NRF2 Modulators in Cancer Therapy

et al. 2020

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The nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.

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“…Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity (83). Furthermore, overexpression of Nrf2, nuclear factor (erytheroid-derived-2)-like 2, increases resistance to the chemotherapeutic drug in breast cancer, acute myeloid leukemia and pancreatic cancer (84)(85)(86). However, the molecular mechanism between them remains further elucidated.…”

Section: Other F-box Proteins Involved In Chemoresistancementioning

confidence: 99%

F‑box proteins involved in cancer‑associated drug resistance (Review)

et al. 2018

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The ubiquitin proteasome system (UPS) regulated human biological processes through the appropriate and efficient proteolysis of cellular proteins. F-box proteins are the vital components of SKP1-CUL1-FBP (SCF)-type E3 ubiquitin ligases that determine substrate specificity. As F-box proteins have the ability to control the degradation of several crucial protein targets associated with drug resistance, the dysregulation of these proteins may lead to induction of chemoresistance in cancer cells. Chemotherapy is one of the most conventional therapeutic approaches of treatment of patients with cancer. However, its exclusive application in clinical settings is restricted due to the development of chemoresistance, which typically results treatment failure. Therefore, overcoming drug resistance is considered as one of the most critical issues that researchers and clinician associated with oncology face. The present review serves to provide a comprehensive overview of F-box proteins and their possible targets as well as their correlation with the chemoresistance and chemosensitization of cancer cells. The article also presents an integrated representation of the complex regulatory mechanisms responsible for chemoresistance, which may lay the foundation to explore sensible candidate drugs for therapeutic intervention.

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Role of NF-E2 related factor 2 (Nrf2) on chemotherapy resistance in acute myeloid leukemia (AML) and the effect of pharmacological inhibition of Nrf2

Cited by 68 publications

References 36 publications

The Potential Role of Nrf2-PD-L1 Axis in Promoting of Oxaliplatin Resistance in Colon Cancer Cells

The Potential Role of Nrf2-PD-L1 Axis in Promoting of Oxaliplatin Resistance in Colon Cancer Cells

Potential Applications of NRF2 Modulators in Cancer Therapy

F‑box proteins involved in cancer‑associated drug resistance (Review)

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