Voriconazole-induced photocarcinogenesis is promoted by aryl hydrocarbon receptor-dependent COX-2 upregulation.

Abstract

Voriconazole (VRCZ) induces the development of UV-associated skin cancers. The mechanism underlying the VRCZ-induced carcinogenesis has been largely unknown. Here, we showed that VRCZ metabolites plus UVA generated reactive oxygen species and resultant DNA damage of the epidermis, but did not induce substantial apoptosis in human keratinocytes (KCs). Furthermore, VRCZ per se stimulates aryl hydrocarbon receptor (AhR) and upregulates COX-2, which is a pivotal enzyme for the promotion of UV-associated tumors, in an AhR-ARNT dependent manner of the classical (genomic) pathway. Our findings suggest that the phototoxic moieties of VRCZ metabolites may participate in the initiation phase of VRCZ skin cancer, while VRCZ per se promotes the tumor development. Therefore, during VRCZ therapy, sun exposure protection is essential to prevent photocarcinogenesis caused by VRCZ metabolites plus UV. Chemoprevention with selective COX-2 inhibitors may be helpful to repress the development of skin cancers derived from DNA-damaged KCs.

• Authors: Shigeki Ikeya, Jun-Ichi Sakabe, Takahiro Yamada, Takafumi Naito, Yoshiki Tokura
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 5050 (03 22 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29568008 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ARNT protein, human
• Reactive Oxygen Species
• Receptors, Aryl Hydrocarbon
• Aryl Hydrocarbon Receptor Nuclear Translocator
• Cyclooxygenase 2
• Voriconazole

Topics

• Apoptosis (drug effects, radiation effects)
• Aryl Hydrocarbon Receptor Nuclear Translocator (genetics)
• Carcinogenesis (drug effects, radiation effects)
• Cyclooxygenase 2 (genetics)
• DNA Damage (drug effects, radiation effects)
• Gene Expression Regulation, Neoplastic (drug effects, radiation effects)
• Humans
• Keratinocytes (drug effects, radiation effects)
• Neoplasms, Radiation-Induced (chemically induced, genetics, pathology)
• Reactive Oxygen Species (metabolism)
• Receptors, Aryl Hydrocarbon (genetics)
• Skin Neoplasms (chemically induced, genetics, pathology)
• Ultraviolet Rays (adverse effects)
• Voriconazole (adverse effects)