Potentiation of cis-dichlorodiammineplatinum (II)-induced cytotoxicity by methylglyoxal.
The dicarbonyl compound methylglyoxal (MG) potentiated the cell inactivating effect of cis-dichlorodiammine-platinum (II) (cis-DDP) when cultured human NHIK 3025 cells were treated with both drugs in simultaneous combination. While a 2 h treatment with cis-DDP alone resulted in a surviving fraction of 0.024 +/- 0.008, the simultaneous presence of 0.5 mM MG, a non-cytotoxic concentration, reduced the fraction of cells surviving treatment to 0.0009 +/- 0.0001. Although the cell inactivating effect of cis-DDP was potentiated, the amount of cell-associated platinum was not affected by MG. Glyoxal, another dicarbonyl compound, did not affect cis-DDP-induced cytotoxicity in any manner, nor did the aliphatic aldehydes acetaldehyde and propionaldehyde. Cell inactivation induced by MG alone at concentrations above 0.5 mM could be prevented by the simultaneous presence of cysteine or glutathione, indicating that cellular sulfhydryls may be involved in the expression of MG-induced cytotoxicity. Furthermore, MG-induced cell inactivation was increased by a dose-modifying factor of 2.6 when NHIK 3025 cells were first pretreated with buthionine sulfoximine, a glutathione synthesis inhibiting compound. We propose that MG reacts with cellular sulfhydryls which may also be involved in the mediation of cis-DDP cytotoxicity. Reactions between cellular sulfhydryls and MG therefore increase the cytotoxicity of cis-DDP by allowing more platinum to react with cellular targets, not by increasing the amount of platinum entering cells.
Dornish
J M
JM
Department of Tissue Culture, Norwegian Radium Hospital, Oslo.
Pettersen
E O
EO
D000447:Aldehydes / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007700:Kinetics; D011765:Pyruvaldehyde / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects*; D002583:Uterine Cervical Neoplasms
D000447:Aldehydes; D011765:Pyruvaldehyde; D002945:Cisplatin