Cisplatin inactivation of caspases inhibits death ligand-induced cell death in vitro and fulminant liver damage in mice.
Cisplatin is a platinum-containing chemotherapeutic drug that has been widely used to treat various human cancers. It acts by forming inter- and intracross-links of DNA, which is believed to be a major cause for its therapeutic efficacy. However, little attention has been paid to the effect of cisplatin on death ligand-induced cell death. Here we demonstrate that cisplatin inhibits death ligand-induced cell death in cell lines in a p53-independent manner. This inhibitory effect of cisplatin on cell death is direct, whereby cisplatin forms a complex with caspases leading to their inactivation. The cisplatin-caspase complex is reversed by the addition of reducing agent dithiothreitol, and caspase activity is regained. In addition, cisplatin shows a death-inhibition effect in in vivo animal models of fulminant liver damage induced by Fas activation and lipopolysaccharide-induced liver shock mediated by tumor necrosis factor-alpha. Together, we demonstrate that cisplatin inhibits cell death induced by death ligands in cell lines and in mice through caspase inactivation.
Shin
Jin Na
JN
Department of Biochemistry, Chosun University School of Medicine, 375 Seosuk-Dong, Dong-Gu, Gwangju, 501-759, Korea.
Seo
Young Woo
YW
Kim
Moonil
M
Park
Sun-Young
SY
Lee
Mi-Ja
MJ
Lee
Byung Rai
BR
Oh
Jae-Wook
JW
Seol
Dai-Wu
DW
Kim
Tae-Hyoung
TH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D004229:Dithiothreitol / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000293:injuries* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000737:chemistry; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C494815:Bid protein, mouse; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases; D002945:Cisplatin; D004229:Dithiothreitol