The research team. Top (from left to right): Steven Wiggerman, Christine Marshall, John T. Seykora, Hasan Bashir, Hiroshi Maeno, Emily Chu. Bottom (from left to right): Xiaoping Yang, Conor O'Day, Steve Prouty, Vivian Lee, Tzvete Dentchev.
By Kristen Mulvihill
Scheie Vision Summer 2020
Clinicians have observed that prolonged use of voriconazole, a frequently prescribed antifungal medication, is linked to the development of cutaneous squamous cell carcinoma (cSCC), the second most common form of cancer. cSCCs, which are associated with chronic sun exposure, can be successfully treated if detected early. However, if left untreated, cSCC has a high risk of invading surrounding tissue and metastasis. These tumors can become dangerous and even life-threatening, with an estimated 3,000 deaths annually in the United States.
cSCCs associated with voriconazole are typically aggressive and develop in sun-exposed skin of the head and neck where vital structures are located. Research has shown that chronic voriconazole use is an independent risk factor for developing these lesions, and unlike typical cSCCs, these lesions can arise in young patients. However, until recently, the mechanism of how this drug causes the aggressive development of cSCCs remained unclear.
A team of researchers led by John T. Seykora, MD, PhD, Associate Professor of Dermatology at the Perelman School of Medicine, published promising breakthroughs in Experimental Dermatology. The team, including co-first author Vivian Lee, MD, Assistant Professor of Ophthalmology and Dermatology, identified a key mechanism that explains the elevated cancer risk caused by voriconazole and a potential therapeutic approach to offset this threat.
Despite its known risk, voriconazole is commonly used in patients with compromised immune systems, such as organ transplant patients, because of its effectiveness in treating and preventing invasive fungal infections. Thus, understanding the mechanism underlying voriconazole-induced cSCC could inform the development of potential treatments that maximize the therapeutic effect of this medication, while minimizing the harmful side effects.
The authors of the study found that voriconazole impairs catalase, a critical enzyme involved in oxidative stress repair. This clue came from a previous study showing that azoles, a molecular structure present in voriconazole, can inhibit catalase in goldfish neurons.
In vitro and in vivo assays supported this hypothesis in skin cells, showing elevation of oxidative stress markers in the presence of voriconazole, which resulted in DNA damage. The researchers concluded that increased levels of oxidative stress are a major source of cellular damage in skin cells and stimulate the formation of cSCCs.
The group then attempted to interfere and mitigate the effects of increased oxidative stress from voriconazole. Human skin cells were pretreated with N-acetylcysteine, a common antioxidant, and then exposed to voriconazole.
“N-acetylcysteine has been used for a variety of purposes and is known to be well-tolerated,” Dr. Lee said. “If a simple intervention such as the co-administration of N-acetylcysteine with voriconazole can reduce this significant side effect, this would help a tremendously vulnerable population.” The researchers observed a significant decrease in oxidative stress markers with N-acetylcysteine, which was confirmed in a unique cSCC genetic mouse model developed by the Seykora lab.
Their data signify a potential therapeutic role for using antioxidants in patients treated with voriconazole. Based on these findings, researchers at Penn are investigating the combination of voriconazole and N-acetylcysteine to minimize the risk of cSCC caused by voriconazole.
“This intervention could serve as a safe and effective treatment for individuals who are prescribed long-term use of the antifungal medication,” explained Dr. Seykora. The team intends to conduct trials in humans to validate the safety and efficacy of this pairing.