ArticleJournal of food and drug analysis2021
A novel NRF2/ARE inhibitor gossypol induces cytotoxicity and sensitizes chemotherapy responses in chemo-refractory cancer cells.
Article in Journal of food and drug analysis, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 9 citations in OpenAlex.
- The impact of oxidative stress and the NRF2-KEAP1-ARE signaling pathway on anticancer drug resistance.Oncology research · 2025Review
- The Role of Nrf2 in the Regulation of Mitochondrial Function and Ferroptosis in Pancreatic Cancer.Antioxidants (Basel, Switzerland) · 2024Review
- The potential roles of gossypol as anticancer agent: advances and future directions.Chinese medicine · 2023Review
- How to deal with frenemy NRF2: Targeting NRF2 for chemoprevention and cancer therapy.Journal of food and drug analysis · 2023Review
- Impact of ROS-Dependent Lipid Metabolism on Psoriasis Pathophysiology.International journal of molecular sciences · 2022Review
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
NRF2/ARE signaling pathway is a principal regulator of cellular redox homoeostasis. The stress-induced transcription factor, NRF2, can shield cells from the oxidative damages via binding to the consensus antioxidant-responsive element (ARE) and driving several cyto-protective genes expression. Increasing evidence indicated that aberrant activation of NRF2 in malignant cells may support their survival through various pathways to detoxify chemotherapy drugs, attenuate drug-induced oxidative stress, or induce drug efflux, all of which are crucial in developing drug resistance. Accordingly, NRF2 is a potential drug target for improving the effectiveness of chemotherapy and to reverse drug resistance in cancer cells. A stable ARE-driven reporter human head and neck squamous cell carcinoma (HNSCC) cell line, HSC3-ARE9, was established and utilized to screen novel NRF2 inhibitors from a compound library. The cotton plant derived phenolic aldehyde-gossypol was selected for further analyses. The effects of gossypol in cancer cells were determined by western blotting, RT-qPCR, clonogenic assay, and cell viability assays. The gossypol-responsive gene expression levels were assessed in the Oncomine database. The effects of gossypol on conferring chemo-sensitization were evaluated in etoposide-resistant and cisplatin-resistant cancer cells. Our study is the first to identify that gossypol is effective to reduce both basal and NRF2 activator tert-butylhydroquinone (t-BHQ)-induced ARE-luciferase activity. Gossypol diminishes NRF2 protein stability and thereby leads to the suppression of NRF2/ARE pathway, which resulted in decreasing the expression levels of NRF2 downstream genes in both time- and dose-dependent manners. Inhibition of NRF2 by gossypol significantly decreases cell viabilities in human cancer cells. In addition, we find that gossypol re-sensitizes topoisomerase II poison treatment in etoposide-resistant cancer cells via suppression of NRF2/ABCC1 axis. Moreover, gossypol suppresses NRF2-mediated G6PD expression thereby leads to induce synthetic lethality with cisplatin not only in parental cancer cells but also in cisplatin-resistant cancer cells. These findings suggest that gossypol is a novel NRF2/ARE inhibitor, and can be a potential adjuvant chemotherapeutic agent for treatment of chemo-refractory tumor.
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