Combination of ebselen and N-acetylcysteine to treat XPC-deficient cells: Oxidative stress, antioxidants and mitochondrial metabolism.

• Grant number: 24/14039-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2025
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Thiago de Souza Freire
• Grantee: Milena Siolin Martins
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Xeroderma pigmentosum complementation groups C (XPC) is a protein that participates in the recognition step of lesions that cause structural alterations in DNA, repaired by the Nucleotide Excision Repair (NER) pathway. Individuals affected by XPC deficiency display hypersensitivity to solar radiation, characterized by higher risk of developing skin cancer, a condition known as xeroderma pigmentosum. However, individuals and animal models deficient in the XPC protein also exhibit phenotypes that are not directly related NER deficiency, suggesting that XPC acts in other pathways and regulates cellular functions independent of DNA repair. Our group showed that XPC deficiency leads to unbalanced mitochondrial respiratory complex usage, with decreased complex I and increased complex II activity. In addition, a greater generation of mitochondrial reactive oxygen species and a decrease in glutathione peroxidase (GPx) activity, an essential factor of antioxidant defenses, were observed. Together these features render XPC-deficient cells more sensitive to compounds that cause oxidative stress. Mechanistically, the increased mitochondrial H2O2 production in XPC cells leads to stabilization and activation of p53 which is responsible for part of the phenotypes associated with XPC deficiency. Moreover, H2O2 plays a central role in the redox unbalance seen in XPC-deficient cells. Thus, we hypothesized that interventions that modulate mitochondrial H2O2 production have the potential to correct the phenotype of XPC-deficient cells. As the absence of XPC is characterized by a decrease in GPx activity, we propose the use of the GPx mimetic, ebselen. Ebselen is one of the most promising GPx mimetic having its peroxidase activity validated in vitro and in vivo, being also the first to be used in clinical trials as an antioxidant and neuroprotective agent, having its efficacy proven.