Targeting the NRF2/KEAP1 pathway in cervical and endometrial cancers

Tossetta, Giovanni; Marzioni, Daniela

doi:10.1016/j.ejphar.2023.175503

Cited by 50 publications

(45 citation statements)

References 155 publications

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“…As mentioned, activation of Nrf2/Keap1 signaling in cancer cells results in chemoresistance, inactivating drug-mediated oxidative stress and protecting cancer cells from drug-induced cell death. According to the obtained results, metformin has an inhibitory effect on Nrf2 and inhibits chemo-resistance in cervical and endometrial cancer [ 155 ].…”

Section: Nrf2/ho-1 Axis Modulating By Natural Antioxidants In Lung Ca...mentioning

confidence: 99%

Modulation of Nrf2/HO-1 by Natural Compounds in Lung Cancer

et al. 2023

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Oxidative stresses (OSs) are considered a pivotal factor in creating various pathophysiological conditions. Cells have been able to move forward by modulating numerous signaling pathways to moderate the defects of these stresses during their evolution. The company of Kelch-like ECH-associated protein 1 (Keap1) as a molecular sensing element of the oxidative and electrophilic stress and nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) as a master transcriptional regulator of the antioxidant response makes a master cytoprotective antioxidant pathway known as the Keap1/Nrf2 pathway. This pathway is considered a dual-edged sword with beneficial features for both normal and cancer cells by regulating the gene expression of the array of endogenous antioxidant enzymes. Heme oxygenase-1 (HO-1), a critical enzyme in toxic heme removal, is one of the clear state indicators for the duality of this pathway. Therefore, Nrf2/HO-1 axis targeting is known as a novel strategy for cancer treatment. In this review, the molecular mechanism of action of natural antioxidants on lung cancer cells has been investigated by relying on the Nrf2/HO-1 axis.

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Section: Nrf2/ho-1 Axis Modulating By Natural Antioxidants In Lung Ca...mentioning

confidence: 99%

Modulation of Nrf2/HO-1 by Natural Compounds in Lung Cancer

et al. 2023

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“…The KEAP1 is a substrate‐recognizing subunit of cullin RING ligase (CRL), responsible for ubiquitylation and subsequent degradation of antioxidant transcription factor nuclear factor erythroid 2‐related factor 2 (Nrf2). 26 , 386 , 387 , 388 , 389 Structurally, KEAP1 mainly consists of an N‐terminal bric‐a‐brac of tramtrack, a broad complex (BTB) domain for cullin 3 binding, and a C‐terminal Kelch domain for substrate recruitment. 390 , 391 , 392 , 393 Recently, a number of small molecules have been shown to modulate the KEAP1/NRF2 axis (Figure 6 ).…”

Section: Keap1 Ligands and Their Utilizations In Protacsmentioning

confidence: 99%

PROTACs: A novel strategy for cancer drug discovery and development

Han

Sun

2023

MedComm

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Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: a small molecule that binds to a target protein, an E3 ligase ligand (consisting of an E3 ligase and its small molecule recruiter), and a chemical linker that hooks first two components together. In the past 20 years, we have witnessed advancement of multiple PRO-TAC degraders into the clinical trials for anticancer therapies. However, one of the major challenges of PROTAC technology is that only very limited number of E3 ligase recruiters are currently available as E3 ligand for targeted protein degradation (TPD), although human genome encodes more than 600 E3 ligases. Thus, there is an urgent need to identify additional effective E3 ligase recruiters for TPD applications. In this review, we summarized the existing RING-type E3 ubiquitin ligase and their small molecule recruiters that act as effective E3 ligands of PRO-TAC degraders and their application in anticancer drug discovery. We believe that this review could serve as a reference in future development of efficient E3 ligands of PROTAC technology for cancer drug discovery and development.

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“…Today, more treatment lines are applied in GC than 1–2 decades before 6 . Multiple exposures to the same agent, such as platinum and taxane, induce oncological resistance with an increase of antioxidant response of the cancer cells 7,8 and can also result in allergic hypersensitivity reactions (HSRs), which affect further treatment and outcomes by necessitating a switch to a less effective and more toxic chemotherapy regimen 9,10 . The antineoplastic agents platinum and taxane together with L‐asparaginase and epipodophyllotoxins have the highest frequency of HSRs 11–13 .…”

Section: Introductionmentioning

confidence: 99%

Desensitization in patients with hypersensitivity to platinum and taxane in gynecological cancers

Zwimpfer,

Scherer,

Schötzau

et al. 2023

Cancer Medicine

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BackgroundExposure to paclitaxel and carboplatin has the risk of developing hypersensitivity reactions (HSRs), which could necessitate using less effective treatments to avoid anaphylaxis. Desensitization to platinum and taxane HSRs can be used to complete chemotherapy according to the standard regimen; therefore, this study investigated rates and benefits of successful desensitization in patients with gynecologic cancers (GC).MethodsWe collected data from 241 patients with GC who had at least one cycle of platinum or taxane chemotherapy. The rate of HSRs and successful desensitization were evaluated, and an outcome analysis was conducted.ResultsThe rate of HSRs to platinum and taxane was 6.39% and 13.07%, respectively. We observed a 100% success rate of desensitization in our cohort. Patients with HSR were significantly younger (57.1 vs. 64.9 years, p = 0.030) in the taxane cohort. Importantly, the overall survival (OS) of patients with platinum and taxane HSRs who underwent desensitization was comparable to that of patients with no HSRs (platinum vs. controls; median OS 60.36 vs. 60.39 months, p = 0.31; taxane vs. controls; OS 80.29 vs. 60.00 months, p = 0.59).ConclusionThus, we show that desensitization for platinum and taxane HSRs is safe and effective, resulting in an outcome that is well comparable to patients without HSR. Based on these observations, desensitization procedures might be considered as standard of care before switching to less effective treatment for patients with GC.

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Targeting the NRF2/KEAP1 pathway in cervical and endometrial cancers

Cited by 50 publications

References 155 publications

Modulation of Nrf2/HO-1 by Natural Compounds in Lung Cancer

Modulation of Nrf2/HO-1 by Natural Compounds in Lung Cancer

PROTACs: A novel strategy for cancer drug discovery and development

Desensitization in patients with hypersensitivity to platinum and taxane in gynecological cancers

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