ArticleRedox biology2017
NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin.
Article in Redox biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 68 citations in OpenAlex.
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- Phenothiazine Derivatives and Their Impact on the Apoptosis Processes: A Review.Journal of applied toxicology : JAT · 2026Review
- Cucurbitacin D Induces Apoptotic Cell Death via NOX4 and Overcomes Radioresistance in Colorectal Cancer.International journal of molecular sciences · 2025Article
- Applications and enhancement strategies of ROS-based non-invasive therapies in cancer treatment.Redox biology · 2025Review
- Prominent Naturally Derived Oxidative-Stress-Targeting Drugs and Their Applications in Cancer Treatment.Antioxidants (Basel, Switzerland) · 2025Review
- Anti-Inflammatory 8-Shogaol Mediates Apoptosis by Inducing Oxidative Stress and Sensitizes Radioresistance in Gastric Cancer.International journal of molecular sciences · 2024Article
- A Novel PPARγ Modulator Falcarindiol Mediates ER Stress-Mediated Apoptosis by Regulating NOX4 and Overcomes Radioresistance in Breast Cancer.Antioxidants (Basel, Switzerland) · 2024Article
- Potential of Natural Products in the Treatment of Glioma: Focus on Molecular Mechanisms.Cell biochemistry and biophysics · 2024Review
- In Silico Analysis of Non-Conventional Oxidative Stress-Related Enzymes and Their Potential Relationship with Carcinogenesis.Antioxidants (Basel, Switzerland) · 2024Article
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- Oxidative State in Cutaneous Melanoma Progression: A Question of Balance.Antioxidants (Basel, Switzerland) · 2024Review
- Beyond Death: Unmasking the Intricacies of Apoptosis Escape.Molecular diagnosis & therapy · 2024Review
- Glutamine-mediated epigenetic regulation of cFLIP underlies resistance to TRAIL in pancreatic cancer.Experimental & molecular medicine · 2024Article
- Role of NADPH Oxidase 4 in Corneal Endothelial Cells Is Mediated by Endoplasmic Reticulum Stress and Autophagy.Antioxidants (Basel, Switzerland) · 2023Article
- Evolution of Natural Product Scaffolds as Potential Proteasome Inhibitors in Developing Cancer Therapeutics.Metabolites · 2023Review
- Curcumin: a natural organic component that plays a multi-faceted role in ovarian cancer.Journal of ovarian research · 2023Review
- Nodakenin Induces ROS-Dependent Apoptotic Cell Death and ER Stress in Radioresistant Breast Cancer.Antioxidants (Basel, Switzerland) · 2023Article
- Active Ingredients from Chinese Medicine for Combination Cancer Therapy.International journal of biological sciences · 2023Review
- Potential ferroptosis-related diagnostic and prognostic biomarkers in laryngeal cancer.European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery · 2022Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Thioridazine is known to have anti-tumor effects by inhibiting PI3K/Akt signaling, which is an important signaling pathway in cell survival. However, thioridazine alone does not induce apoptosis in head and neck squamous cell carcinoma (AMC-HN4), human breast carcinoma (MDA-MB231), and human glioma (U87MG) cells. Therefore, we investigated whether combined treatment with thioridazine and curcumin induces apoptosis. Combined treatment with thioridazine and curcumin markedly induced apoptosis in cancer cells without inducing apoptosis in human normal mesangial cells and human normal umbilical vein cells (EA.hy926). We found that combined treatment with thioridazine and curcumin had synergistic effects in AMC-HN4 cells. Among apoptosis-related proteins, thioridazine plus curcumin induced down-regulation of c-FLIP and Mcl-1 expression at the post-translational levels in a proteasome-dependent manner. Augmentation of proteasome activity was related to the up-regulation of proteasome subunit alpha 5 (PSMA5) expression in curcumin plus thioridazine-treated cells. Combined treatment with curcumin and thioridazine produced intracellular ROS in a NOX4-dependent manner, and ROS-mediated activation of Nrf2/ARE signaling played a critical role in the up-regulation of PSMA5 expression. Furthermore, ectopic expression of c-FLIP and Mcl-1 inhibited apoptosis in thioridazine and curcumin-treated cells. Therefore, we demonstrated that thioridazine plus curcumin induces proteasome activity by up-regulating PSMA5 expression via NOX4-mediated ROS production and that down-regulation of c-FLIP and Mcl-1 expression post-translationally is involved in apoptosis.
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