Cyclosporin A, but not everolimus, inhibits DNA repair mediated by calcineurin: implications for tumorigenesis under immunosuppression

Abstract

Unlike other immunosuppressive drugs including everolimus, cyclosporin A causes a dramatic increase of UVinduced 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 signallingdependent impairment of NER.

Purpuric macules and plaques in a patient with myasthenia gravis

“…From an immunological point of view, corticosteroids enhance KS cell growth by either reactivating a preexisting HHV8 infection or by inhibiting activation of transforming growth factor β (TGF-β ), which is involved in lymphocyte proliferation [9,10]. Considering this pathway, switching immunosuppressive therapy in MG to mTOR inhibitors, such as sirolimus or everolimus, might be an option to reduce the possibility of iatrogenic KS [ 4,11,12 ] .…”

“…While human herpesvirus type 8 (HHV-8) is frequently found in KS patients, other factors have also been implicated in its pathogenesis, including concomitant immunological dysfunction frequently related to HIV infection [ 8 ] or immunosuppressive agents [ 1 ] . Cyclosporine and corticosteroids are the most common immunosuppressants associated with iatrogenic Kaposi's sarcoma [ 3,5,[9][10][11][12] . In our patient, histopathology revealed positive immunostaining for HHV8 (Figure 2 d).…”

Purpuriforme Maculae und Plaques bei einem Patienten mit Myasthenia gravis

“…Vom immunologischen Standpunkt verstärken Kortikosteroide das Zellwachstum des KS entweder durch Reaktivierung einer vorbestehenden HHV-8-Infektion oder durch Hemmung der Aktivierung von transforming growth factor β (TGF-β ), der an der Lymphozytenproliferation beteiligt ist [ 9,10 ] . In Anbetracht dieses Signalwegs könnte bei der MG der Wechsel der immunsuppressiven Therapie zu mTOR-Inhibitoren wie Sirolimus oder Everolimus eine Option sein, um das Risiko eines iatrogenen KS zu verringern [ 4,11,12 ] .In seinen frühen Stadien wird das KS klinisch häufi g mit ausgedehnten Ekchymosen und Petechien, fi xen Arzneimittelexanthemen, lichenoider Pigmentpurpura, bazillärer Angiomatose, Akroangiodermatitis oder dem Pseudo-Kaposi-Sarkom verwechselt.Zusammenfassend ist im Rahmen einer immunsuppressiven Therapie bei Patienten mit Myasthenia gravis eine engmaschige Nachbeobachtung nötig, um Malignome frühzeitig zu erkennen. Das Auftreten kutaner oder mukosaler Läsio-nen sollte immer Anlass zu einer hautärztlichen Konsultation geben, um eine frühe Diagnose des iatrogenen KS zu ermög-lichen und um bei der Entscheidung zu helfen, ob eine immunsuppressive Therapie niedriger dosiert oder gewechselt werden sollte.…”

“…Vom immunologischen Standpunkt verstärken Kortikosteroide das Zellwachstum des KS entweder durch Reaktivierung einer vorbestehenden HHV-8-Infektion oder durch Hemmung der Aktivierung von transforming growth factor β (TGF-β ), der an der Lymphozytenproliferation beteiligt ist [ 9,10 ] . In Anbetracht dieses Signalwegs könnte bei der MG der Wechsel der immunsuppressiven Therapie zu mTOR-Inhibitoren wie Sirolimus oder Everolimus eine Option sein, um das Risiko eines iatrogenen KS zu verringern [ 4,11,12 ] .…”

Functional and molecular genetic analyses of nine newly identified XPD‐deficient patients reveal a novel mutation resulting in TTD as well as in XP/CS complex phenotypes

“…Cellular post-UV cell survival was assessed after UVC irradiation (0-30 J/m 2 ) applying the MTT assay (14,15). Plasmid host cell reactivation (HCR) to determine the cellular NER capacity and complementation group assignment were performed as described (14,16).…”