Inhibitors of Nucleotide Excision Repair Decrease UVB-Induced Mutagenesis-An In Vitro Study.
Int J Mol Sci
; 22(4)2021 Feb 06.
Article
en En
| MEDLINE
| ID: mdl-33562002
ABSTRACT
The high incidence of skin cancers in the Caucasian population is primarily due to the accumulation of DNA damage in epidermal cells induced by chronic ultraviolet B (UVB) exposure. UVB-induced DNA photolesions, including cyclobutane-pyrimidine dimers (CPDs), promote mutations in skin cancer driver genes. In humans, CPDs are repaired by nucleotide excision repair (NER). Several commonly used and investigational medications negatively influence NER in experimental systems. Despite these molecules' ability to decrease NER activity in vitro, the role of these drugs in enhancing skin cancer risk is unclear. In this study, we investigated four molecules (veliparib, resveratrol, spironolactone, and arsenic trioxide) with well-known NER-inhibitory potential in vitro, using UVB-irradiated CHO epithelial and HaCaT immortalized keratinocyte cell lines. Relative CPD levels, hypoxanthine phosphoribosyltransferase gene mutation frequency, cell viability, cell cycle progression, and protein expression were assessed. All four molecules significantly elevated CPD levels in the genome 24 h after UVB irradiation. However, veliparib, spironolactone, and arsenic trioxide reduced the mutagenic potential of UVB, while resveratrol did not alter UVB-induced mutation formation. UVB-induced apoptosis was enhanced by spironolactone and arsenic-trioxide treatment, while veliparib caused significantly prolonged cell cycle arrest and increased autophagy. Spironolactone also enhanced the phosphorylation level of mammalian target of rapamycin (mTOR), while arsenic trioxide modified UVB-driven mitochondrial fission. Resveratrol induced only mild changes in the cellular UVB response. Our results show that chemically inhibited NER does not result in increased mutagenic effects. Furthermore, the UVB-induced mutagenic potential can be paradoxically mitigated by NER-inhibitor molecules. We identified molecular changes in the cellular UVB response after NER-inhibitor treatment, which may compensate for the mitigated DNA repair. Our findings show that metabolic cellular response pathways are essential to consider in evaluating the skin cancer risk-modifying effects of pharmacological compounds.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Espironolactona
/
Rayos Ultravioleta
/
Bencimidazoles
/
Daño del ADN
/
Reparación del ADN
/
Resveratrol
/
Trióxido de Arsénico
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Int J Mol Sci
Año:
2021
Tipo del documento:
Article
País de afiliación:
Hungria