Vulnerability of Antioxidant Drug Therapies on Targeting the Nrf2-Trp53-Jdp2 Axis in Controlling Tumorigenesis

• Published in: Cells (Basel, Switzerland) Switzerland), 2024-10, Vol.13 (19), p.1648
• Main Authors: Lin, Ying-Chu, Ku, Chia-Chen, Wuputra, Kenly, Wu, Deng-Chyang, Yokoyama, Kazunari K
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; Antioxidants - metabolism; Antioxidants - pharmacology; antioxidation; Apoptosis; Bladder; Breast cancer; Cancer therapies; cancer therapy; Carcinogenesis - drug effects; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell cycle; Cell death; Cell survival; Colorectal cancer; Defense mechanisms; Development and progression; Dimerization; Drug delivery; Drug resistance; Drug therapy; Drugs; Enzymes; Esophagus; heterogeneity; Homeostasis; Humans; Hypoxia; Ligands; Malignancy; Medical prognosis; Metabolic rate; Metabolism; Metabolites; Metastasis; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; NF-E2-Related Factor 2 - metabolism; Organoids; Oxidation; Oxidative stress; Oxidative Stress - drug effects; Proteins; Proto-Oncogene Mas; Reactive oxygen species; Reactive Oxygen Species - metabolism; redox homeostasis; Review; Signal Transduction - drug effects; Success; Toxicity; Tumor suppressor genes; tumor suppressor p53; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors; Urogenital system
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13191648

Control of oxidation/antioxidation homeostasis is important for cellular protective functions, and disruption of the antioxidation balance by exogenous and endogenous ligands can lead to profound pathological consequences of cancerous commitment within cells. Although cancers are sensitive to antioxidation drugs, these drugs are sometimes associated with problems including tumor resistance or dose-limiting toxicity in host animals and patients. These problems are often caused by the imbalance between the levels of oxidative stress-induced reactive oxygen species (ROS) and the redox efficacy of antioxidants. Increased ROS levels, because of abnormal function, including metabolic abnormality and signaling aberrations, can promote tumorigenesis and the progression of malignancy, which are generated by genome mutations and activation of proto-oncogene signaling. This hypothesis is supported by various experiments showing that the balance of oxidative stress and redox control is important for cancer therapy. Although many antioxidant drugs exhibit therapeutic potential, there is a heterogeneity of antioxidation functions, including cell growth, cell survival, invasion abilities, and tumor formation, as well as the expression of marker genes including tumor suppressor proteins, cell cycle regulators, nuclear factor erythroid 2-related factor 2, and Jun dimerization protein 2; their effectiveness in cancer remains unproven. Here, we summarize the rationale for the use of antioxidative drugs in preclinical and clinical antioxidant therapy of cancer, and recent advances in this area using cancer cells and their organoids, including the targeting of ROS homeostasis.