title: Cyclosporine a induces growth arrest or programmed cell death of human glioma cells.
abstract: Human malignant gliomas are highly resistant to current therapeutic approaches. We previously demonstrated that cyclosporine A (CsA) induces an apoptotic cell death in rat C6 glioma cells. In the present study, we found the induction of growth arrest or cell death of human malignant glioma cells exposed to CsA. In studied glioma cells, an accumulation of p21Cip1/Waf1 protein, a cell cycle inhibitor, was observed following CsA treatment, even in the absence of functional p53 tumour suppressor. CsA induced a senescence-associated growth arrest, in U87-MG glioma cells with functional p53, while in U373 and T98G glioma cells with mutated p53, CsA treatment triggered cell death associated with alterations of cell morphology, cytoplasm vacuolation, and condensation of chromatin. In T98G cells this effect was completely abolished by simultaneous treatment with an inhibitor of protein synthesis, cycloheximide (CHX). Moreover, CsA-induced cell death was accompanied by activation of executory caspases followed by PARP cleavage. CsA treatment did not elevate fasL expression and had no effect on mitochondrial membrane potential. We conclude that CsA triggers either growth arrest or non-apoptotic, programmed cell death in human malignant glioma cells. Moreover, CsA employs mechanisms different to those in the action of radio- and chemotherapeutics, and operating even in cells resistant to conventional treatments. Thus, CsA or related drugs may be an effective novel strategy to treat drug-resistant gliomas or complement apoptosis-based therapies.
authors.affiliation: Laboratory of Transcription Regulation, Department Cell Biology, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Zupanska
authors.forename: Magdalena
authors.initials: M
authors.lastname: Dziembowska
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Ellert-Miklaszewska
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gaweda-Walerych
authors.forename: Bozena
authors.initials: B
authors.lastname: Kaminska
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D024161:Collagen Type XI / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002843:Chromatin; D024161:Collagen Type XI; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; C066455:PARP protein, Bos taurus; D011500:Protein Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; D016572:Cyclosporine; D020169:Caspases