Immunosuppressant deoxyspergualin induces apoptotic cell death in dividing cells.
Deoxyspergualin (DSG) has been found to have an antitumour and immunosuppressive activity. However, the precise mechanism of action of DSG has not been clarified. We have used its analogue, methyldeoxyspergualin (MeDSG) for in vitro culture studies of DSG since it shows good stability in aqueous solution and retains strong immunosuppressive activity. In the present study, we found that MeDSG inhibited proliferation of rapidly dividing murine T-cell hybridomas, resulting in cell death. The cell death was accompanied by chromatin condensation and DNA cleavage at the linker regions between nucleosomes. Furthermore, MeDSG induced a reduction in mitochondrial transmembrane potential. When murine thymocytes were treated with MeDSG for 48 hr, a slight increase of DNA fragmentation was constantly observed, and selective depletion of CD4- CD8- cells was noticed. In contrast, CD4+ CD8+ cells were hardly affected. Moreover, splenic T-cells are resistant to MeDSG-induced apoptosis, as evaluated by measuring DNA cleavage. Our findings may account for the immunosuppressive and antitumour properties of DSG which were described in a number of previous studies.
Odaka
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C
Department of Bacterial and Blood Products, National Institute of Infectious Diseases, Tokyo, Japan.
Toyoda
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E
Nemoto
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006825:Hybridomas; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects*; D013950:Thymus Gland / Q000276:immunology
D000903:Antibiotics, Antineoplastic; D006146:Guanidines; D007166:Immunosuppressive Agents; C037258:gusperimus