Title: Voriconazole enhances UV-induced DNA damage by inhibiting catalase and promoting oxidative stress.
Authors: Lee, Vivian; Gober, Michael D; Bashir, Hasan; O'Day, Conor; Blair, Ian A; Mesaros, Clementina; Weng, Liwei; Huang, Andrew; Chen, Aaron; Tang, Rachel; Anagnos, Vince; Li, JiLon; Roling, Sophie; Sagaityte, Emilija; Wang, Andrew; Lin, Chenyan; Yeh, Christopher; Atillasoy, Cem; Marshall, Christine; Dentchev, Tzvete; Ridky, Todd; Seykora, John T
Published In Exp Dermatol, (2020 01)
Abstract: Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer and is associated with cumulative UV exposure. Studies have shown that prolonged voriconazole use promotes cSCC formation; however, the biological mechanisms responsible for the increased incidence remain unclear. Here, we show that voriconazole directly increases oxidative stress in human keratinocytes and promotes UV-induced DNA damage as determined by comet assay, 8-oxoguanine immunofluorescence and mass spectrometry. Voriconazole treatment of human keratinocytes potentiates UV-induced apoptosis and activation of the p38 MAP kinase and 53BP1 UV stress response pathways. The p38 MAP kinase activation promoted by voriconazole exposure can be mitigated by pretreating keratinocytes with N-acetylcysteine. Voriconazole increases oxidative stress in keratinocytes by directly inhibiting catalase leading to lower intracellular NADPH levels and the triazole moieties in voriconazole are critical for inhibiting catalase. Furthermore, voriconazole is shown to promote UV-induced dysplasia in an in vivo model. Together, these data demonstrate that voriconazole potentiates oxidative stress in UV-irradiated keratinocytes through catalase inhibition. Use of antioxidants may mitigate the pro-oncogenic effects of voriconazole.
PubMed ID: 31519066
MeSH Terms: 8-Hydroxy-2'-Deoxyguanosine/metabolism; Acetylcysteine/pharmacology; Animals; Antifungal Agents/pharmacology*; Apoptosis/drug effects; Apoptosis/radiation effects; Carcinogenesis/drug effects; Carcinogenesis/radiation effects; Catalase/antagonists & inhibitors; Cell Proliferation/drug effects; Cells, Cultured; DNA Damage/drug effects*; DNA Damage/radiation effects; Humans; Keratinocytes/physiology; MAP Kinase Signaling System/drug effects; MAP Kinase Signaling System/radiation effects; Mice; Oxidative Stress/drug effects*; Primary Cell Culture; Skin/drug effects; Skin/metabolism; Skin/pathology; Skin/radiation effects; Terbinafine/pharmacology; Tumor Suppressor p53-Binding Protein 1/metabolism; Ultraviolet Rays/adverse effects*; Voriconazole/pharmacology*