The use of calcineurin inhibitors in solid organ transplantation results in an increased risk of skin cancer. We examined the effect of these drugs on DNA repair in normal human keratinocytes after ultraviolet B (UVB) irradiation. We found that both cyclosporine A (CsA) and ascomycin inhibited removal of cyclobutane pyrimidine dimers, and that they also inhibited UVB-induced apoptosis. We also observed that UVB induced nuclear localization of the transcription factor nuclear factor of activated T-cells (NFAT), and that this was blocked by CsA and ascomycin. These data suggest that the increased risk of skin cancer observed in organ-transplant patients may be as a result of not only systemic immune suppression but also the local inhibition of DNA repair and apoptosis in skin by calcineurin inhibitors. These findings may have implications for the use of topical calcineurin inhibitors in sun-exposed skin and eyes.

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Calcineurin inhibitors are drugs used to suppress the immune system by blocking the nuclear localization of the NFAT transcription factor. Systemic use of these drugs is essential to organ transplantation, but comes at the cost of elevated rates of skin cancer. They have been used topically in atopic dermatitis and other skin diseases on the assumption that they avoid the cancer risk by localized use. The results here show that in skin cells and artificial models of human skin, calcineurin inhibitors block UV-induced nuclear localization of NFAT, and significantly reduce repair of cyclobutane pyrimidine dimers induced in DNA. In addition they inhibit apoptosis of UV-irradiated cells. The effect of blocking nuclear localization of NFAT and inhibiting DNA repair should be considered in judging the risk of topical use of calcineurin inhibitors.

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