For the last decade, medical experts have known that voriconazole—an antifungal medication used to prevent infections in patients with compromised immune systems—is linked to the development of particularly aggressive squamous cell carcinoma in skin exposed to ultraviolet (UV) rays. However, the mechanism of how voriconazole causes cutaneous squamous cell carcinoma was unclear. Now a team has shown that voriconazole increases levels of oxidative stress in skin cells called keratinocytes, and that a common antioxidant, N-acetylcysteine, can mitigate voriconazole’s cancer-inducing side effect in keratinocytes. Their findings were published by Lee et al in Experimental Dermatology.
Methods and Findings
The research team conducted studies in both cell cultures and animal models to examine the cellular effects of voriconazole in combination with UV exposure. Using a clue from a prior study on goldfish neurons where the compound azole was found to inhibit the antioxidative enzyme catalase, the team hypothesized that voriconazole would have the same effect on catalase in the skin because it contains an azole moiety. Inhibition of catalase would then induce higher levels of oxidative stress in skin cells, promoting the formation of cutaneous squamous cell carcinoma. Utilizing various assays and a unique genetic mouse model, this study proved the researchers’ hypothesis to be correct.
The team went on to pretreat human skin cells in culture with N-acetylcysteine, an antioxidant, to help mitigate the effects of increased oxidative stress. The team found that the antioxidant reduced two markers of oxidative stress in mouse skin tissue exposed to UV radiation.
“Once we knew what the relationship between voriconazole and catalase was, we could attempt to interfere with it and diminish the effects,” said senior study author John T. Seykora, MD, PhD.
This finding sets the stage for trials pairing voriconazole with an antioxidant to see if the combination decreases rates of cutaneous squamous cell carcinoma and if it could serve as an effective treatment for those who have to take the antifungal drug.
“Conducting human trials to show that the combination of voriconazole and N-acetylcysteine is safe and effective is the next step in this research. Since N-acetylcysteine has existed for years and is a common treatment for other conditions, we anticipate a safe pairing,” said Dr. Seykora. “People with suppressed immune systems already have other medical concerns to worry about. We don’t want them to have to worry about elevated skin cancer risk, too.”
Disclosure: The work was supported by the National Institutes of Health and a Dermatology Foundation CDA Award. For full disclosures of the study authors, visit onlinelibrary.wiley.com.
