Cyclosporin A potentiates the cytotoxic effects of methyl methanesulphonate in HL-60 and K562 cells.
Methyl methanesulphonate (MMS) is a DNA damaging agent, which induces oxidative stress, ATP depletion, and consequently, cell death, in HL-60 and K562 cells. The cell death induced by MMS predominantly exhibited the morphological and biochemical hallmarks of necrosis. A minor population of dying cells exhibited apoptotic hallmarks, especially in K562 cell cultures. Cyclosporin A (CsA) was used to modulate the MMS-induced cell death. Our results indicated that CsA did not prevent cells from dying, but changed the mode of death from necrotic to apoptotic. Surprisingly, CsA enhanced oxidative stress and increased the overall number of dead cells. Based on these results, we conclude that the modulatory effect of CsA on MMS-induced cell death might arise from an interference by CsA with mitochondrial metabolism, rather than from inhibition of the MMS efflux mediated by P-glycoprotein.
Mlejnek
Petr
P
Department of Biology, Faculty of Medicine, Palacky University, Olomouc, Czech Republic. mlejnek_petr@volny.cz
Frydrych
Ivo
I
Dolezel
Petr
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000096:biosynthesis; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000633:toxicity*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D018922:HL-60 Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D020014:K562 Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008741:Methyl Methanesulfonate / Q000633:toxicity*; D009336:Necrosis / Q000139:chemically induced; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004273:DNA, Neoplasm; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016572:Cyclosporine; D008741:Methyl Methanesulfonate; D053148:Caspase 3; D005978:Glutathione; D019803:Glutathione Disulfide