Upregulation of NOX-2 and Nrf-2 Promotes 5-Fluorouracil Resistance of Human Colon Carcinoma (HCT-116) Cells

Waghela, Bhargav N.; Vaidya, Foram U.; Pathak, Chandramani

doi:10.1134/s0006297921030044

Cited by 12 publications

(8 citation statements)

References 44 publications

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“…One explanation for the anti-tumour role of Nrf2 relies on its antioxidant capacity, which renders tumour cells less sensitive to drugs that induce oxidative stress overcoming the typically high ROS threshold of tumours. Accordingly, many lines of evidence indicate that Nrf2 overactivity is implicated in chemoresistance to different conventional drugs including cisplatin [ 78 ], 5-fluorouracil [ 79 ], doxorubicin [ 80 ], vincristine [ 81 ], etoposide [ 82 ] and mitoxantrone [ 83 ].…”

Section: The Dual Role Of Nrf2 In Cancermentioning

confidence: 99%

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

Emanuele

Celesia

D’Anneo

et al. 2021

IJMS

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known transcription factor best recognised as one of the main regulators of the oxidative stress response. Beyond playing a crucial role in cell defence by transactivating cytoprotective genes encoding antioxidant and detoxifying enzymes, Nrf2 is also implicated in a wide network regulating anti-inflammatory response and metabolic reprogramming. Such a broad spectrum of actions renders the factor a key regulator of cell fate and a strategic player in the control of cell transformation and response to viral infections. The Nrf2 protective roles in normal cells account for its anti-tumour and anti-viral functions. However, Nrf2 overstimulation often occurs in tumour cells and a complex correlation of Nrf2 with cancer initiation and progression has been widely described. Therefore, if on one hand, Nrf2 has a dual role in cancer, on the other hand, the factor seems to display a univocal function in preventing inflammation and cytokine storm that occur under viral infections, specifically in coronavirus disease 19 (COVID-19). In such a variegate context, the present review aims to dissect the roles of Nrf2 in both cancer and COVID-19, two widespread diseases that represent a cause of major concern today. In particular, the review describes the molecular aspects of Nrf2 signalling in both pathological situations and the most recent findings about the advantages of Nrf2 inhibition or activation as possible strategies for cancer and COVID-19 treatment respectively.

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Section: The Dual Role Of Nrf2 In Cancermentioning

confidence: 99%

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

Emanuele

Celesia

D’Anneo

et al. 2021

IJMS

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“…HO-1 has also been implicated in therapy resistance in a variety of cancers, including CRC [21,22]. As mentioned before, this ability of cancers to escape therapy has been attributed to the existence of subpopulations of CSCs, which activate DNA repair, increase drug efflux, and their quiescent state [23].…”

Section: Introductionmentioning

confidence: 96%

Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53

Ríos‐Arrabal

Puentes-Pardo

Moreno-SanJuan

et al. 2021

JPM

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Heme oxygenase-1 (HO-1) is an antioxidant protein implicated in tumor progression, metastasis, and resistance to therapy. Elevated HO-1 expression is associated with stemness in several types of cancer, although this aspect has not yet been studied in colorectal cancer (CRC). Using an in vitro model, we demonstrated that HO-1 overexpression regulates stemness and resistance to 5-FU treatment, regardless of p53. In samples from CRC patients, HO-1 and endothelin converting enzyme-1 (ECE-1) expression correlated significantly, and p53 had no influence on this result. Carbon monoxide (CO) activated the ECE-1/endothelin-1 (ET-1) pathway, which could account for the protumoral effects of HO-1 in p53 wild-type cells, as demonstrated after treatment with bosentan (an antagonist of both ETRA and ETRB endothelin-1 receptors). Surprisingly, in cells with a non-active p53 or a mutated p53 with gain-of-function, ECE-1-produced ET-1 acted as a protective molecule, since treatment with bosentan led to increased efficiency for spheres formation and percentage of cancer stem cells (CSCs) markers. In these cells, HO-1 could activate or inactivate certain unknown routes that could induce these contrary responses after treatment with bosentan in our cell model. However more research is warranted to confirm these results. Patients carrying tumors with a high expression of both HO-1 and ECE-1 and a non-wild-type p53 should be considered for HO-1 based-therapies instead of ET-1 antagonists-based ones.

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“…Oxidative stress and ROS metabolism have been repeatedly described in the context of drug resistance [66][67][68]. We consistently found that ROS metabolism is a potential Achilles' heel in acquired drug resistance of neuroblastoma models and highlight the possible use of APR-246 in the targeted treatment of vulnerabilities that are a consequence of chemoresistance.…”

Section: Discussionmentioning

confidence: 66%

Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma

Müller

Rösch

Najafi

et al. 2021

Cancers

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APR-246 (Eprenetapopt/PRIMA-1Met) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we investigated the responses of approximately 800 cancer cell lines (50 entities; Cancer Therapeutics Response Portal, CTRP) to APR-246 treatment. In particular, neuroblastoma, lymphoma and acute lymphocytic leukemia cells were highly responsive. With gene expression data from the Cancer Cell Line Encyclopedia (CCLE; n = 883) and patient samples (n = 1643) from the INFORM registry study, we confirmed that these entities express low levels of SLC7A11, a previously described predictive biomarker for APR-246 responsiveness. Combining the CTRP drug response data with the respective CCLE gene expression profiles, we defined a novel gene signature, predicting the effectiveness of APR-246 treatment with a sensitivity of 90% and a specificity of 94%. We confirmed the predicted APR-246 sensitivity in 8/10 cell lines and in ex vivo cultures of patient samples. Moreover, the combination of ROS detoxification-impeding APR-246 with approved HDAC-inhibitors, known to elevate ROS, substantially increased APR-246 sensitivity in cell cultures and in vivo in two zebrafish neuroblastoma xenograft models. These data provide evidence that APR-246, in combination with HDAC-inhibitors, displays a novel potent targeted treatment option for neuroblastoma patients.

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Upregulation of NOX-2 and Nrf-2 Promotes 5-Fluorouracil Resistance of Human Colon Carcinoma (HCT-116) Cells

Cited by 12 publications

References 44 publications

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

Endothelin-1 as a Mediator of Heme Oxygenase-1-Induced Stemness in Colorectal Cancer: Influence of p53

Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma

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