Department of Dermatology, Venerology, and Allergology, Georg-August-University, Goettingen, Germany.
Exp Dermatol. 2011 Mar;20(3):232-6. doi: 10.1111/j.1600-0625.2010.01213.x.
Unlike other immunosuppressive drugs including everolimus, cyclosporin A causes a dramatic increase of UV-induced skin cancer, a feature that is reminiscent of xeroderma pigmentosum (XP), where defective nucleotide excision repair (NER) of UV-induced DNA damage results in cutaneous carcinogenesis. The molecular basis of the clinically important differential activities of cyclosporin A and everolimus is still unclear. We measured post-UV cell survival of cyclosporin A- and everolimus-treated human fibroblasts and lymphoblasts using a cell proliferation assay (MTT). The cellular NER capacity was assessed by host cell reactivation. Using an ELISA and specific antibodies, cyclobutane pyrimidine and pyrimidine-6,4-pyrimidone photoproduct removal from the cellular genome was measured. The effect of calcineurin on NER was investigated using a calcineurin A expression vector and specific RNAi. Cyclosporin A led to a dose dependent decrease in post-UV cell survival, inhibited NER and blocked photoproduct removal. In contrast, none of these effects where seen in everolimus-treated cells. Overexpression of calcineurin A resulted in increased NER and complemented the Cyclosporin A-induced reduction of NER. Downregulation of calcineurin using RNAi inhibited NER comparable to cyclosporin A-treatment. We conclude that cyclosporin A, but not everolimus, leads to an increased skin cancer risk via a calcineurin signalling-dependent impairment of NER.
与其他免疫抑制剂（如依维莫司）不同，环孢素 A 会导致 UV 诱导的皮肤癌显著增加，这一特征类似于色素性干皮病（XP），其中 UV 诱导的 DNA 损伤的核苷酸切除修复（NER）缺陷导致皮肤癌发生。环孢素 A 和依维莫司临床重要的差异活性的分子基础仍不清楚。我们使用细胞增殖测定法（MTT）测量了环孢素 A 和依维莫司处理的人成纤维细胞和淋巴母细胞的 UV 后细胞存活率。通过宿主细胞复活评估细胞 NER 能力。使用 ELISA 和特异性抗体，从细胞基因组中测量环丁烷嘧啶和嘧啶-6,4-嘧啶酮光产物的去除。使用钙调神经磷酸酶表达载体和特异性 RNAi 研究钙调神经磷酸酶对 NER 的影响。环孢素 A 导致 UV 后细胞存活率呈剂量依赖性下降，抑制 NER 并阻断光产物去除。相比之下，在依维莫司处理的细胞中没有观察到这些作用。钙调神经磷酸酶的过表达导致 NER 增加，并补充了环孢素 A 诱导的 NER 减少。使用 RNAi 下调钙调神经磷酸酶可抑制 NER，与环孢素 A 处理相当。我们得出结论，环孢素 A 而不是依维莫司通过钙调神经磷酸酶信号依赖性 NER 损伤导致皮肤癌风险增加。
