Cyclosporine and skin cancer: an international dermatologic perspective over 25 years of experience. A comprehensive review and pursuit to define safe use of cyclosporine in dermatology.
ABSTRACT Cyclosporine A (CsA), a powerful immunosuppressant drug effective in treating a variety of dermatologic diseases, is often avoided due to potential adverse side effects such as skin cancer. CsA-induced skin cancers are well documented in organ transplant literature. This association is less clear when dermatologic guidelines are followed (e.g., low dose, healthy patients, time-limited use, no other immunosuppressive agents, etc.). Marcil and Stern estimated increased risk of squamous cell carcinoma (SCC) after CsA treatment equivalent to 200 PUVA treatments while the original data collected by Sandoz Ltd. reported a significantly less skin malignancies at doses of 5 mg/kg/day or less. Reviewing 60 studies and over 1700 patients in 25 years of existing US and international multicenter studies revealed 63 patients (less than 1%) with skin cancer. No skin cancers were reported with 6 months continuous use or up to 2 years of intermittent therapy. PUVA phototherapy overwhelmingly preceded CsA use in reported cases. Overall, 14 case reports were found suggesting CsA-induced skin cancers with the majority either having violated accepted dermatologic safety guidelines or enrolling patients with significant pre-existing carcinogenic risk factors. When reviewing over 25 years of dermatologic experience worldwide, it is not clearly substantiated that skin cancer risk is necessarily increased in patients using CsA.
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ABSTRACT: Since nuclear factor of activated T cells (NFAT) was first identified as a transcription factor in T cells, various NFAT isoforms have been discovered and investigated. Accumulating studies have suggested that NFATs are involved in many aspects of cancer, including carcinogenesis, cancer cell proliferation, metastasis, drug resistance and tumor microenvironment. Different NFAT isoforms have distinct functions in different cancers. The exact function of NFAT in cancer or the tumor microenvironment is context dependent. In this review, we summarize our current knowledge of NFAT regulation and function in cancer development and treatment. NFATs have emerged as a potential target for cancer prevention and therapy. Copyright © 2015. Published by Elsevier Ireland Ltd.
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ABSTRACT: Members of the nuclear factor of activated T cells (NFAT) family have been identified as regulators of oncogenic transformation in several human malignancies. A prominent member of this family, NFAT1, is associated with tumor cell survival, apoptosis, migration and invasion. Here, we investigated the role of NFAT1 in glioma cells. In 111 clinical samples, microarray analysis demonstrated that NFAT1 was over-expressed in glioblastoma multiforme (GBM), compared with low-grade gliomas, a result confirmed by RT-PCR in 24 clinical samples and in the U87 and U251 cell lines. Immunohistochemistry and immunofluorescence stain indicated that over-expressed NFAT1 was mainly located in the nucleus, where it acted as a transcription factor. After treatment with the NFAT antagonist cyclosporin A (CsA) and FK506, levels of NFAT1 in the nuclei of U87 GBM cells were dramatically reduced. The invasive potential of U87 cells was reduced by the same treatment, as well as by inhibition of NFAT1 expression using small hairpin RNA. Proliferation of U87 cells was unaffected by CsA, FK506 and NFAT1 shRNA transfection. Clustering analysis and Pearson correlation analysis of microarray data showed that the expression of NFAT1 correlated with the expression of the invasion-related genes cyclooxygenase-2 (COX-2), matrix metalloproteinase-7 (MMP-7) and MMP-9, a result confirmed by in vitro analysis. These findings demonstrate that NFAT1 contributes to the invasive potential but not the proliferation of GBM cells, and suggest that CsA may find application as an adjuvant in combined treatment strategies for GBM.PLoS ONE 06/2013; 8(6):e66008. DOI:10.1371/journal.pone.0066008 · 3.53 Impact FactorThis article is viewable in ResearchGate's enriched formatRG Format enables you to read in context with side-by-side figures, citations, and feedback from experts in your field.
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ABSTRACT: Cyclosporine A (CsA) is one of the most effective systemic drugs available for the treatment of psoriasis, as evidenced by the results of several randomized studies and by a prolonged experience in dermatological setting. In clinical practice, CsA is usually used for the induction of psoriasis remission at a daily dose included in the range of 2.5-5 mg/kg and with intermittent short-term regimens, lasting on average 3-6 months. The magnitude and rapidity of response are dose dependent, as well as the risk of development of adverse events. Therefore, the dose should be tailored to patient's needs and general characteristics and adjusted during the treatment course according to both the efficacy and tolerability. Some studies support the feasibility of pulse administration of CsA for a few days per week for both the induction and the maintenance of response in psoriasis patients. This paper will review the data on CsA regimens for plaque-type psoriasis and will focus the attention on dose, treatment duration, novel schedules, and role in combination therapies, including the association with biologicals.The Scientific World Journal 07/2013; 2013:805705. DOI:10.1155/2013/805705 · 1.22 Impact FactorThis article is viewable in ResearchGate's enriched formatRG Format enables you to read in context with side-by-side figures, citations, and feedback from experts in your field.