title: 2-Chlorodeoxyadenosine (cladribine) induces apoptosis in human monocyte-derived dendritic cells.
abstract: 2-Chlorodeoxyadenosine (cladribine, CdA) is an immunosuppressive drug that is licensed to treat hairy cell leukaemia, and has been shown recently to have beneficial effects in patients with multiple sclerosis (MS). The therapeutic effects of CdA have been suggested to be mediated partly through its potent toxicity towards lymphocytes. However, the effects of CdA on other immune cells are poorly understood. In the present study, we investigated the effects of CdA on the induction of apoptosis in human monocytes, monocyte-derived immature (ImDC) and mature (mDC) dendritic cells. Treatment of monocytes with CdA strongly induced apoptosis after 24 h, while apoptosis induction in DC was evident after 72 h. Furthermore, CdA treatment strongly induced caspase-3 and caspase-9 in monocytes, whereas activation of caspases was undetected in DC. The mitochondrial membrane potential in DC was reduced significantly after CdA treatment. DNA hypodiploid assessment showed fragmented nuclei in DC after CdA treatment together with activation of p53 protein. These results revealed that CdA induces caspase-independent apoptosis in DC and suggest cell type specific effects of CdA. This mechanism may contribute to the effect of CdA in autoimmune diseases.
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Singh
authors.forename: C K
authors.initials: CK
authors.lastname: Prajeeth
authors.forename: V
authors.initials: V
authors.lastname: Gudi
authors.forename: K
authors.initials: K
authors.lastname: Bénardais
authors.forename: E V
authors.initials: EV
authors.lastname: Voss
authors.forename: M
authors.initials: M
authors.lastname: Stangel
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D017338:Cladribine / Q000494:pharmacology* / Q000627:therapeutic use; D004249:DNA Damage / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007943:Leukemia, Hairy Cell / Q000188:drug therapy*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D009103:Multiple Sclerosis / Q000188:drug therapy*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D016159:Tumor Suppressor Protein p53; D017338:Cladribine; D053148:Caspase 3; D053453:Caspase 9
keywords: DNA fragmentation; caspases; cladribine; mitochondrial potential; phosphatidylserine