The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells

Silva, Matheus Molina; Rocha, Clarissa Ribeiro Reily; Kinker, Gabriela Sarti; Pelegrini, Alessandra Luíza; Menck, Carlos Frederico Martins

doi:10.1038/s41598-019-54065-6

Cited by 88 publications

(64 citation statements)

References 36 publications

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“…Recently, NRF2 activity was shown to be involved in the autophagy process [48,49] as well as mesenchymal transition and invasion in several tumors including glioblastoma [50,51]. Emerging research has demonstrated that hyperactivation of the NRF2 pathway enables protection against chemotherapeutic agents, creating an environment that favors the survival of malignant cells [19,52,53].…”

Section: Discussionmentioning

confidence: 99%

Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries

Rocha

Silva

et al. 2020

Cells

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Glioblastoma is a severe type of brain tumor with a poor prognosis and few therapy options. Temozolomide (TMZ) is one of these options, however, with limited success, and failure is mainly due to tumor resistance. In this work, genome-wide CRISPR-Cas9 lentiviral screen libraries for gene knockout or activation were transduced in the human glioblastoma cell line, aiming to identify genes that modulate TMZ resistance. The sgRNAs enriched in both libraries in surviving cells after TMZ treatment were identified by next-generation sequencing (NGS). Pathway analyses of gene candidates on knockout screening revealed several enriched pathways, including the mismatch repair and the Sonic Hedgehog pathways. Silencing three genes ranked on the top 10 list (MSH2, PTCH2, and CLCA2) confirm cell protection from TMZ-induced death. In addition, a CRISPR activation library revealed that NRF2 and Wnt pathways are involved in TMZ resistance. Consistently, overexpression of FZD6, CTNNB1, or NRF2 genes significantly increased cell survival upon TMZ treatment. Moreover, NRF2 and related genes detected in this screen presented a robust negative correlation with glioblastoma patient survival rates. Finally, several gene candidates from knockout or activation screening are targetable by inhibitors or small molecules, and some of them have already been used in the clinic.

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Section: Discussionmentioning

confidence: 99%

Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries

Rocha

Silva

et al. 2020

Cells

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“…Indeed the upregulation of NRF2 (nuclear factor, erythroid-derived 2-like 2 factor) has been observed in a wide array of tumors including breast, ovarian, prostate, skin, lung and pancreas [ 32 , 44 ]. NRF2 is a master regulator of antioxidant response as a transcription factor regulating expression of several enzymes responsible for glutathione synthesis, including glutamate-cysteine ligase modifier subunit (GCLM) and the glutamate-cysteine catalytic subunit (GCLC), as well as enzymes related to GSH utilization, such as glutathione reductase, glutathione peroxidase and glutathione S transferase (GST) [ 45 , 46 ].…”

Section: Glutathione Redox and Ros In Healthy And Tumor Cellsmentioning

confidence: 99%

Role of Glutathione in Cancer: From Mechanisms to Therapies

et al. 2020

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Glutathione (GSH) is the most abundant non-protein thiol present at millimolar concentrations in mammalian tissues. As an important intracellular antioxidant, it acts as a regulator of cellular redox state protecting cells from damage caused by lipid peroxides, reactive oxygen and nitrogen species, and xenobiotics. Recent studies have highlighted the importance of GSH in key signal transduction reactions as a controller of cell differentiation, proliferation, apoptosis, ferroptosis and immune function. Molecular changes in the GSH antioxidant system and disturbances in GSH homeostasis have been implicated in tumor initiation, progression, and treatment response. Hence, GSH has both protective and pathogenic roles. Although in healthy cells it is crucial for the removal and detoxification of carcinogens, elevated GSH levels in tumor cells are associated with tumor progression and increased resistance to chemotherapeutic drugs. Recently, several novel therapies have been developed to target the GSH antioxidant system in tumors as a means for increased response and decreased drug resistance. In this comprehensive review we explore mechanisms of GSH functionalities and different therapeutic approaches that either target GSH directly, indirectly or use GSH-based prodrugs. Consideration is also given to the computational methods used to describe GSH related processes for in silico testing of treatment effects.

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“…Increased GSH has long been considered as an accomplice in the progression and multidrug resistance of cancer [122][123][124][125][126]. GSH depletion obtained by the irreversible GCL inhibitor BSO is the most commonly used method and is associated with many chemotherapy drugs.…”

Section: Modulate Ros Generation and Elimination Tomentioning

confidence: 99%

ROS-Mediated Therapeutic Strategy in Chemo-/Radiotherapy of Head and Neck Cancer

Huang

Pan

2020

Oxidative Medicine and Cellular Longevity

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Head and neck cancer is a highly genetic and metabolic heterogeneous collection of malignancies of the lip, oral cavity, salivary glands, pharynx, esophagus, paranasal sinuses, and larynx with five-year survival rates ranging from 12% to 93%. Patients with head and neck cancer typically present with advanced stage III, IVa, or IVb disease and are treated with comprehensive modality including chemotherapy, radiotherapy, and surgery. Despite advancements in treatment modality and technique, noisome recurrence, invasiveness, and resistance as well as posttreatment complications severely influence survival rate and quality of life. Thus, new therapeutic strategies are urgently needed that offer enhanced efficacy with less toxicity. ROS in cancer cells plays a vital role in regulating cell death, DNA repair, stemness maintenance, metabolic reprogramming, and tumor microenvironment, all of which have been implicated in resistance to chemo-/radiotherapy of head and neck cancer. Adjusting ROS generation and elimination to reverse the resistance of cancer cells without impairing normal cells show great hope in improving the therapeutic efficacy of chemo-/radiotherapy of head and neck cancer. In the current review, we discuss the pivotal and targetable redox-regulating system including superoxide dismutases (SODs), tripeptide glutathione (GSH), thioredoxin (Trxs), peroxiredoxins (PRXs), nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/keap1), and mitochondria electron transporter chain (ETC) complexes and their roles in regulating ROS levels and their clinical significance implicated in chemo-/radiotherapy of head and neck cancer. We also summarize several old drugs (referred to as the non-anti-cancer drugs used in other diseases for a long time) and small molecular compounds as well as natural herbs which effectively modulate cellular ROS of head and neck cancer to synergize the efficacy of conventional chemo-/radiotherapy. Emerging interdisciplinary techniques including photodynamic, nanoparticle system, and Bio-Electro-Magnetic-Energy-Regulation (BEMER) therapy are promising measures to broaden the potency of ROS modulation for the benefit of chemo-/radiotherapy in head and neck cancer.

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The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells

Cited by 88 publications

References 36 publications

Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries

Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries

Role of Glutathione in Cancer: From Mechanisms to Therapies

ROS-Mediated Therapeutic Strategy in Chemo-/Radiotherapy of Head and Neck Cancer

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