bims-nurfca Biomed News
on NRF2 and Cancer
Issue of 2023‒06‒18
twelve papers selected by
Caner Geyik
Istinye University
  1. Role of Natural and Synthetic Compounds in Modulating NRF2/KEAP1 Signaling Pathway in Prostate Cancer.
  2. Nrf2 targeting in overcoming ferroptosis evasion in head and neck cancer.
  3. Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinoma.
  4. Targeting Nrf2 for ferroptosis-based therapy: Implications for overcoming ferroptosis evasion and therapy resistance in cancer.
  5. Human papillomavirus-driven repression of NRF2 signalling confers chemo-radio sensitivity and predicts prognosis in head and neck squamous cell carcinoma.
  6. SMURF1 attenuates endoplasmic reticulum stress by promoting the degradation of KEAP1 to activate NRF2 antioxidant pathway.
  7. The synergistic effects of PRDX5 and Nrf2 on lung cancer progression and drug resistance under oxidative stress in the zebrafish models.
  8. NRF2/HO-1 axis, BIRC5, and TP53 expression in ESCC and its correlation with clinical pathological characteristics and prognosis.
  9. Amelioratory effects of astragaloside IV on hepatocarcinogenesis via Nrf2-mediated pSmad3C/3L transformation.
  10. The role of biomarkers in stage III non-small cell lung cancer.
  11. RXR agonist, Bexarotene, effectively reduces drug resistance via regulation of RFX1 in embryonic carcinoma cells.
  12. Cancer Prevention and Therapy by Targeting Oxidative Stress Pathways.
  1. Cancers (Basel). 2023 Jun 02. pii: 3037. [Epub ahead of print]15(11):
    Role of Natural and Synthetic Compounds in Modulating NRF2/KEAP1 Signaling Pathway in Prostate Cancer.
    Giovanni Tossetta, Sonia Fantone, Daniela Marzioni, Roberta Mazzucchelli.
      Prostate cancer is the second most common cancer in men worldwide. Prostate cancer can be treated by surgery or active surveillance when early diagnosed but, when diagnosed at an advanced or metastatic stage, radiation therapy or androgen-deprivation therapy is needed to reduce cancer progression. However, both of these therapies can cause prostate cancer resistance to treatment. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development, progression and treatment resistance. The nuclear factor erythroid 2-related factor 2 (NRF2)/KEAP1 (Kelch-Like ECH-Associated Protein 1) pathway plays an important role in protecting cells against oxidative damage. Reactive oxygen species (ROS) levels and NRF2 activation can determine cell fate. In particular, toxic levels of ROS lead physiological cell death and cell tumor suppression, while lower ROS levels are associated with carcinogenesis and cancer progression. On the contrary, a high level of NRF2 promotes cell survival related to cancer progression activating an adaptive antioxidant response. In this review, we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 signaling pathway in prostate cancer.
    Keywords:  KEAP1; NRF2; antioxidants; chemotherapy; compounds; natural; prostate cancer; signaling; synthetic
    DOI:  https://doi.org/10.3390/cancers15113037
  2. Biochem Biophys Res Commun. 2023 Jun 07. pii: S0006-291X(23)00767-2. [Epub ahead of print]671 225-228
    Nrf2 targeting in overcoming ferroptosis evasion in head and neck cancer.
    Jong-Lyel Roh.
      Ferroptosis is a recently identified type of regulated cell death characterized by lipid peroxidation and redox-active iron accumulation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulator of genes involved in glutathione biosynthesis, antioxidant responses, lipid metabolism, and iron metabolism, contributing to the evasion of ferroptosis. Inhibiting the Nrf2 pathway has been shown to sensitize cancer cells to ferroptosis. In head and neck cancer cells, we found that activation of the Nrf2-antioxidant responsive element pathway leads to ferroptosis resistance, and inhibiting this pathway reverses ferroptosis evasion. Our study suggests that modulating the Nrf2 pathway could be a promising strategy to overcome resistance in cancer therapy for head and neck cancer. Further research is required to investigate the potential of ferroptosis induction in therapy-resistant head and neck cancer. Targeting Nrf2 through ferroptosis-based cancer therapy may be a novel and effective approach to reverse the resistance of head and neck cancer therapy.
    Keywords:  Ferroptosis; Head and neck cancer; Nuclear factor erythroid 2-related factor 2; Resistance; Therapy
    DOI:  https://doi.org/10.1016/j.bbrc.2023.06.022
  3. Front Pharmacol. 2023 ;14 1176819
    Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinoma.
    Suchisnigdha Datta, Anupam Bishayee, Dona Sinha.
      Constitutive activation of nuclear factor erythroid 2-related factor 2 (NRF2) is pivotal in bestowing therapy resistance in cancer cells. Several phytochemicals have been reported with the potential of modulating NRF2. Therefore, it was hypothesized that NRF2-deregulated chemoresistance in lung adenocarcinoma (LUAD) may be counteracted by theaflavin-rich black tea (BT). A non-responsive LUAD cell line, A549, was the best sensitized towards cisplatin upon pre-treatment with BT. BT-mediated NRF2 reorientation was observed to be dependent on concentration and duration of treatment as well as on the mutational profile of NRF2 in A549 cells. Transient exposure of low-concentration BT hormetically downregulated NRF2, its downstream antioxidants, and drug transporter. BT also influenced the Kelch-like ECH-associated protein (KEAP1)-dependent cullin 3 (Cul3) and KEAP-1-independent signaling through epidermal growth factor receptor (EGFR) - rat sarcoma virus (RAS) - rapidly accelerated fibrosarcoma (RAF) - extracellular signal-regulated kinase 1/2 (ERK) - matrix metalloproteinase (MMP)-2 and MMP-9. The realignment of NRF2 in KEAP1-suppressed A549 cells enhanced the chemotherapeutic outcome. But a higher concentration of the same BT surprisingly upregulated NRF2 and its transcriptional targets with a subsequent decrease in the NRF2-regulatory machinery in NCI-H23 cells (a KEAP1-overexpressed LUAD cell line), ultimately resulting in a better anticancer response. The BT-mediated bidirectional NRF2 modulation was reconfirmed upon comparison with the action of a pharmacological NRF2 inhibitor, ML-385, in A549 and a known NRF2 activator, tertiary-butylhydroquinone, in NCI-H23 respectively. BT-mediated regulation of NRF2-KEAP1 and their upstream networks (EGFR/RAS/RAF/ERK) sufficed as a better anticancer agent than synthetic NRF2 modulators. Therefore, BT may be indicated as a potent multi-modal small molecule for increasing drug responsiveness in LUAD cells by maintaining NRF2/KEAP1 axis at an optimum level.
    Keywords:  KEAP1; NRF2; black tea; chemoresistance; lung adenocarcinoma; redox signaling; treatment
    DOI:  https://doi.org/10.3389/fphar.2023.1176819
  4. Biochim Biophys Acta Mol Basis Dis. 2023 Jun 10. pii: S0925-4439(23)00154-0. [Epub ahead of print]1869(7): 166788
    Targeting Nrf2 for ferroptosis-based therapy: Implications for overcoming ferroptosis evasion and therapy resistance in cancer.
    Jaewang Lee, Jong-Lyel Roh.
      Ferroptosis is a newly discovered form of programmed cell death caused by redox-active iron-mediated lipid peroxidation. Ferroptosis exhibits a unique morphological phenotype resulting from oxidative damage to membrane lipids. Ferroptosis induction has been shown to be effective in treating human cancers that rely on lipid peroxidation repair pathways. Nuclear factor erythroid 2-related factor 2 (Nrf2) can control the regulatory pathways of ferroptosis, which involve genes associated with glutathione biosynthesis, antioxidant responses, and lipid and iron metabolism. Resistant cancer cells often utilize Nrf2 stabilization by Keap1 inactivation or other somatic alterations in the genes from the Nrf2 pathway, which can confer resistance to ferroptosis induction and other therapies. However, pharmacological inactivation of the Nrf2 pathway can sensitize cancer cells to ferroptosis induction. Inducing lipid peroxidation and ferroptosis through regulating the Nrf2 pathway is a promising strategy for enhancing the anticancer effects of chemotherapy and radiation therapy in therapy-resistant human cancers. Despite promising preliminary studies, clinical trials in human cancer therapy have not yet been realized. A deeper understanding of their exact processes and efficacies in various cancers remains unsolved. Therefore, this article aims to summarize the regulatory mechanisms of ferroptosis, their modulation by Nrf2, and the potential of targeting Nrf2 for ferroptosis-based cancer therapy.
    Keywords:  Cancer; Ferroptosis; Nuclear factor erythroid 2-related factor 2; Resistance; Therapy
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166788
  5. Free Radic Biol Med. 2023 Jun 14. pii: S0891-5849(23)00497-5. [Epub ahead of print]
    Human papillomavirus-driven repression of NRF2 signalling confers chemo-radio sensitivity and predicts prognosis in head and neck squamous cell carcinoma.
    Pushkal S Ramesh, Venugopal R Bovilla, Vikas H Swamy, Nandini N Manoli, Krishnappa B Dasegowda, Siddegowda M Siddegowda, Shilpa Chandrashekarappa, Vishveshwara M Somasundara, K Shyama Prasada, R Rajesh, Devanand Devegowda, Rajesh K Thimmulappa.
      PURPOSE: To investigate the role of NRF2 signalling in conferring superior prognosis in patients with HPV positive (HPV + ve) head & neck squamous cell carcinomas (HNSCC) compared to HPV negative (HPV-ve) HNSCC and develop molecular markers for selection of HPV + ve HNSCC patients for treatment de-escalation trials.METHODS: NRF2 activity (NRF2, KEAP1, and NRF2-transcriptional targets), p16, and p53 levels between HPV + ve HNSCC and HPV-ve HNSCC in prospective and retrospective tumor samples as well as from TCGA database were compared. Cancer cells were transfected with HPV-E6/E7 plasmid to elucidate if HPV infection represses NRF2 activity and sensitizes to chemo-radiotherapy.
    RESULTS: Prospective analysis revealed a marked reduction in expression of NRF2, and its downstream genes in HPV + ve tumors compared to HPV-ve tumors. A retrospective analysis by IHC revealed significantly lower NQO1 in p16high tumors compared to p16low tumors and the NQO1 expression correlated negatively with p16 and positively with p53. Analysis of the TCGA database confirmed low constitutive NRF2 activity in HPV + ve HNSCC compared to HPV-ve HNSCC and revealed that HPV + ve HNSCC patients with 'low NQO1' expression showed better overall survival compared to HPV + ve HNSCC patients with 'high NQO1' expression. Ectopic expression of HPV-E6/E7 plasmid in various cancer cells repressed constitutive NRF2 activity, reduced total GSH, increased ROS levels, and sensitized the cancer cells to cisplatin and ionizing radiation.
    CONCLUSION: Low constitutive NRF2 activity contributes to better prognosis of HPV + ve HNSCC patients. Co-expression of p16high, NQO1low, and p53low could serve as a predictive biomarker for the selection of HPV + ve HNSCC patients for de-escalation trials.
    Keywords:  HPV; Head and neck cancer; NQO1; NRF2; Prognostic biomarkers; Treatment de-escalation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.06.011
  6. Cell Death Dis. 2023 Jun 14. 14(6): 361
    SMURF1 attenuates endoplasmic reticulum stress by promoting the degradation of KEAP1 to activate NRF2 antioxidant pathway.
    Lei Dong, Mengchuan Xu, Yang Li, Wanting Xu, Chengwei Wu, Hanfei Zheng, Zhenyu Xiao, Guochen Sun, Lei Ding, Xiaobo Li, Wenming Li, Liying Zhou, Qin Xia.
      Cancer cells consistently utilize the unfolded protein response (UPR) to encounter the abnormal endoplasmic reticulum (ER) stress induced by the accumulation of misfolded proteins. Extreme activation of the UPR could also provoke maladaptive cell death. Previous reports have shown that NRF2 antioxidant signaling is activated by UPR and serves as noncanonical pathway to defense and reduce excessive ROS levels during ER stress. However, the mechanisms of regulating NRF2 signaling upon ER stress in glioblastoma have not been fully elucidated. Here we identify that SMURF1 protects against ER stress and facilitates glioblastoma cell survival by rewiring KEAP1-NRF2 pathway. We show that ER stress induces SMURF1 degradation. Knockdown of SMURF1 upregulates IRE1 and PERK signaling in the UPR pathway and prevents ER-associated protein degradation (ERAD) activity, leading to cell apoptosis. Importantly, SMURF1 overexpression activates NRF2 signaling to reduce ROS levels and alleviate UPR-mediated cell death. Mechanistically, SMURF1 interacts with and ubiquitinates KEAP1 for its degradation (NRF2 negative regulator), resulting in NRF2 nuclear import. Moreover, SMURF1 loss reduces glioblastoma cell proliferation and growth in subcutaneously implanted nude mice xenografts. Taken together, SMURF1 rewires KEAP1-NRF2 pathway to confer resistance to ER stress inducers and protect glioblastoma cell survival. ER stress and SMURF1 modulation may provide promising therapeutic targets for the treatment of glioblastoma.
    DOI:  https://doi.org/10.1038/s41419-023-05873-2
  7. Oncol Res. 2022 ;30(2): 53-64
    The synergistic effects of PRDX5 and Nrf2 on lung cancer progression and drug resistance under oxidative stress in the zebrafish models.
    Sitong Qian, Ying Fang, Chengyun Yao, Yongsheng Wang, Zhi Zhang, Xiaohua Wang, Jin Gao, Yong Feng, Lei Sun, Runyue Zou, Guoren Zhou, Jinjun Ye, Ruixue Xia, Hongping Xia.
      Previous studies have shown that PRDX5 and Nrf2 are antioxidant proteins related to abnormal reactive oxidative species (ROS). PRDX5 and Nrf2 play a critical role in the progression of inflammations and tumors. The combination of PRDX5 and Nrf2 was examined by Co-immunoprecipitation, western blotting and Immunohistochemistry. H2O2 was applied to affect the production of ROS and induced multi-resistant protein 1 (MRP1) expression in NSCLC cells. The zebrafish models mainly investigated the synergistic effects of PRDX5 and Nrf2 on lung cancer drug resistance under oxidative stress. We showed that PRDX5 and Nrf2 form a complex and significantly increase the NSCLC tissues compared to adjacent tissues. The oxidative stress improved the combination of PRDX5 and Nrf2. We demonstrated that the synergy between PRDX5 and Nrf2 is positively related to the proliferation and drug resistance of NSCLC cells in the zebrafish models. In conclusion, our data indicated that PRDX5 could bind to Nrf2 and has a synergistic effect with Nrf2. Meanwhile, in the zebrafish models, PRDX5 and Nrf2 have significant regulatory impacts on lung cancer progression and drug resistance activities under oxidative stress.
    Keywords:  Drug resistance; Lung cancer; Nrf2; Oxidative stress; PRDX5; Zebrafish models
    DOI:  https://doi.org/10.32604/or.2022.026302
  8. Int J Biol Markers. 2023 Jun 14. 3936155231176571
    NRF2/HO-1 axis, BIRC5, and TP53 expression in ESCC and its correlation with clinical pathological characteristics and prognosis.
    Yongmei Gao, Li Wan, Mengyan Li, Bo Wang, Yuqing Ma.
      BACKGROUND: Many types of cancer exhibit high nuclear factor erythroid 2-related factor 2 (NRF2), which is effective in resisting drugs and radiation. However, the role of NRF2 gene expression in predicting the prognosis of esophageal squamous cell carcinoma (ESCC) remains unclear.METHODS: The association between NRF2, heme oxygenase-1 (HO-1), baculovirus IAP repeat 5 (BIRC5), P53 gene expression levels and their relationship to immune-infiltrating cells were assessed using the Cancer Genome Atlas dataset, the Human Protein Atlas and the TISDB database. The expression of NRF2, HO-1, BIRC5, and TP53 in 118 ESCC patients was detected by immunohistochemistry, and the relationship between their expression level and clinicopathological parameters and prognosis was analyzed.
    RESULTS: In ESCC, NRF2 overexpression was significantly associated with Han ethnicity, lymph node metastasis, and distant metastasis. HO-1 overexpression was significantly associated with differentiation, advanced clinical staging, lymph node metastasis, nerve invasion, and distant metastasis. BIRC5 overexpression was significantly associated with Han ethnicity and lymph node metastasis. TP53 overexpression was significantly associated with Han ethnicity and T staging. The NRF2/HO-1 axis expression was positively correlated with BIRC5 and TP53. Kaplan-Meier and multivariate Cox regression analysis showed that NRF2, BIRC5, and TP53 genes co-expression was an independent prognostic risk factor. TISIDB dataset analysis showed that immune-infiltrating cells were significantly negatively correlated with NRF2 and BIRC5.
    CONCLUSION: NRF2, BIRC5, and TP53 axis gene expressions are predictors of poor prognosis for ESCC. The overexpression of the NRF2/HO-1/BIRC5 axis may not be related to immune-infiltrating cells.
    Keywords:  BIRC5; NRF2; co-expression; esophageal squamous cell carcinoma; lymph node metastasis; prognosis
    DOI:  https://doi.org/10.1177/03936155231176571
  9. Phytomedicine. 2023 May 29. pii: S0944-7113(23)00264-7. [Epub ahead of print]117 154903
    Amelioratory effects of astragaloside IV on hepatocarcinogenesis via Nrf2-mediated pSmad3C/3L transformation.
    Yong Fang Gong, Shu Hou, Jia-Cheng Xu, Yan Chen, Le-Le Zhu, Ying-Ying Xu, Yu-Qing Chen, Miao-Miao Li, Li-Li Li, Jing-Jing Yang, Yan Yang.
      BACKGROUND: Phosphorylated Smad3 isoforms are reversible and antagonistic, and the tumour-suppressive pSmad3C can shift to an oncogenic pSmad3L signal. In addition, Nrf2 has a two-way regulatory effect on tumours, protecting normal cells from carcinogens and promoting tumour cell survival in chemotherapeutics. Accordingly, we hypothesised that the transformation of pSmad3C/3L is the basis for Nrf2 to produce both pro- and/or anti-tumourigenic effects in hepatocarcinogenesis. Astragaloside IV (AS-IV), the major component of Astragalus membranaceus, exerts anti-fibrogenic and carcinogenic actions. Lately, AS-IV administration could delay the occurrence of primary liver cancer by persistently inhibiting the fibrogenesis and regulating pSmad3C/3 L and Nrf2/HO-1 pathways synchronously. However, effect of AS-IV on hepatocarcinogenesis implicated in the bidirectional cross-talking of pSmad3C/3 L and Nrf2/HO-1 signalling, especially which one contributes palpably than the other still remains unclear.PURPOSE: This study aims to settle the above questions by using in vivo (pSmad3C+/- and Nrf2-/- mice) and in vitro (plasmid- or lentivirus- transfected HepG2 cells) models of HCC.
    STUDY DESIGN AND METHODS: The correlation of Nrf2 to pSmad3C/pSmad3L in HepG2 cells was analysed by Co-immunoprecipitation and dual-luciferase reporter assay. Pathological changes of Nrf2, pSmad3C, and pSmad3L in human HCC patients, pSmad3C+/- mice, and Nrf2-/- mice were gauged by immunohistochemical, haematoxylin and eosin staining, Masson, and immunofluorescence assays. Finally, western blot and qPCR were used to verify the bidirectional cross-talking of pSmad3C/3L and Nrf2/HO-1 signalling protein and mRNA in vivo and in vitro models of HCC.
    RESULTS: Histopathological manifestations and biochemical indicators revealed that pSmad3C+/- could abate the ameliorative effects of AS-IV on fibrogenic/carcinogenic mice with Nrf2/HO-1 deactivation and pSmad3C/p21 transform to pSmad3L/PAI-1//c-Myc. As expected, cell experiments confirmed that upregulating pSmad3C boosts the inhibitory activity of AS-IV on phenotypes (cell proliferation, migration and invasion), followed by a shift of pSmad3L to pSmad3C and activation of Nrf2/HO-1. Synchronously, experiments in Nrf2-/- mice and lentivirus-carried Nrf2shRNA cell echoed the results of pSmad3C knockdown. Complementarily, Nrf2 overexpression resulted in the opposite result. Furthermore, Nrf2/HO-1 contributes to AS-IV's anti-HCC effect palpably compared with pSmad3C/3L.
    CONCLUSION: These studies highlight that harnessing the bidirectional crosstalk pSmad3C/3 L and Nrf2/HO-1, especially Nrf2/HO-1 signalling, acts more effectively in AS-IV's anti-hepatocarcinogenesis, which may provide an important theoretical foundation for the use of AS-IV against HCC.
    Keywords:  AS-IV; Hepatocarcinogenesis; Nrf2; Oxidative stress; pSmad3C
    DOI:  https://doi.org/10.1016/j.phymed.2023.154903
  10. Expert Rev Respir Med. 2023 Jun 15. 1-12
    The role of biomarkers in stage III non-small cell lung cancer.
    Rafael Rosell, María González-Cao, Masaoki Ito, Mariacarmela Santarpia, Andrés Aguilar, Jordi Codony-Servat.
      INTRODUCTION: Stage III non-small cell lung cancer (NSCLC) is a composite of the regional spread of lung cancer with different levels of potential lymph node involvement and tumor size that often deem the stage at time of diagnosis to be unresectable and suitable for chemoradiation plus consolidation immunotherapy with durvalumab for 12 months. Chemoradiation plus durvalumab consolidation yielded a landmark 49.2% 5-year overall survival in unresectable NSCLC.AREAS COVERED: Sub-optimal results lead us to focus on the mechanisms of resistance responsible for intractability in a significant proportion of cases that fail with chemoradiation and immunotherapy. In stage III NSCLC it is opportune to explore the accumulated evidence on ferroptosis resistance that can lead to cancer progression and metastasis. Strong data shows that three anti-ferroptosis pathways are principally involved in resistance to chemotherapy, radiation, and immunotherapy.
    EXPERT OPINION: Because a large part of stage III NSCLCs is resistant to chemoradiation and durvalumab consolidation, a ferroptosis-based therapeutic approach, combined with standard-of-care therapy, can lead to improved clinical outcomes in patients diagnosed with stage III and possibly stage IV NSCLCs.
    Keywords:  DHODH; Durvalumab, SLC17A11; KEAP1; NRF2; Stage III NSCLC; chemoradiation; ferroptosis; p53
    DOI:  https://doi.org/10.1080/17476348.2023.2223985
  11. Biochim Biophys Acta Mol Cell Res. 2023 Jun 09. pii: S0167-4889(23)00082-4. [Epub ahead of print]1870(7): 119510
    RXR agonist, Bexarotene, effectively reduces drug resistance via regulation of RFX1 in embryonic carcinoma cells.
    Joby Issac, Pooja S Raveendran, Midhunaraj Kunnummal, Mary Angelin, Swathy Ravindran, Budhaditya Basu, Ani V Das.
      Aberrant expression of multidrug resistance (MDR) proteins is one of the features of cancer stem cells (CSCs) that make them escape chemotherapy. A well-orchestrated regulation of multiple MDRs by different transcription factors in cancer cells confers this drug resistance. An in silico analysis of the major MDR genes revealed a possible regulation by RFX1 and Nrf2. Previous reports also noted that Nrf2 is a positive regulator of MDR genes in NT2 cells. But we, for the first time, report that Regulatory factor X1 (RFX1), a pleiotropic transcription factor, negatively regulates the major MDR genes, Abcg2, Abcb1, Abcc1, and Abcc2, in NT2 cells. The levels of RFX1 in undifferentiated NT2 cells were found to be very low, which significantly increased upon RA-induced differentiation. Ectopic expression of RFX1 reduced the levels of transcripts corresponding to MDRs and stemness-associated genes. Interestingly, Bexarotene, an RXR agonist that acts as an inhibitor of Nrf2-ARE signaling, could increase the transcription of RFX1. Further analysis revealed that the RFX1 promoter has binding sites for RXRα, and upon Bexarotene exposure RXRα could bind and activate the RFX1 promoter. Bexarotene, alone or in combination with Cisplatin, could inhibit many cancer/CSC-associated properties in NT2 cells. Also, it significantly reduced the expression of drug resistance proteins and made the cells sensitive towards Cisplatin. Our study proves that RFX1 could be a potent molecule to target MDRs, and Bexarotene can induce RXRα-mediated RFX1 expression, therefore, would be a better chemo-assisting drug during therapy.
    Keywords:  Bexarotene; Multidrug resistance; Nrf2; RFX1
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119510
  12. Molecules. 2023 May 24. pii: 4293. [Epub ahead of print]28(11):
    Cancer Prevention and Therapy by Targeting Oxidative Stress Pathways.
    Sarmistha Saha, Luciano Saso, Guliz Armagan.
      Oxidative stress arises from the inadequate production of reactive oxygen species (ROS) which couldn't be neutralized by antioxidant defense [...].
    DOI:  https://doi.org/10.3390/molecules28114293
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