Cyclosporin D is a hydroxylated metabolite of cyclosporin A. Cyclosporin D and other cyclosporin metabolites have been found to have lower (<10%) immunosuppressant activity than cyclosporin A. Cyclosporin D has been found to reverse daunorubicin resistance in some resistant leukemia cells by possibly inhibiting the efflux functions of P-glycoprotein.
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|Mechanism of Action||Cyclosporin B (and other cyclosporin A metabolites) have lower immunosuppressive activity but likely operate under the same mechanism as cyclosporin A described below. |
After entering a T-cell, Cyclosporin A associates with the cytosolic protein cyclophilin which helps in protein folding. Cyclosporin A binds to cyclophilins and this complex binds another cytosolic protein phosphatase called Calcineurin (protein phosphatase 2B) that dephosphorylates a transcription factor (nuclear factor of activated T-cells, or NF-AT) needed for expression of interleukin 2 (IL-2.). It also blocks the pathway to nitric oxide synthesis via tumor necrosis factor (TNFa) and Interleukin 1a.
|Cancer Applications||Cyclosporin’s immunosuppressive properties and potential toxicity can be studied during in vitro assays. Other metabolites of Cyclosporin A (AM1, AM1c, DihydroAM1, AM19, and AM4N) can also be studied (Vollenbroeker B et al, 2005).|
|References||Anderson MA and Gusella JF (1984) Use of Cyclosporin A in establishing Epstein-Barr virus-transformed human lymphoblastoid cell lines. In Vitro 20(11):856-858. PMID 6519667 |
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