title: Cisplatin, oxaliplatin, and carboplatin unequally inhibit in vitro mRNA translation.
abstract: DNA is considered the preferential target of platinum containing cytostatics such as cisplatin, oxaliplatin, and carboplatin. Despite profound knowledge on the interaction between platinum drugs and DNA, there is little data on the interaction with mRNA and even less on the potential differences among these antineoplastic agents to inhibit protein synthesis. We therefore established an in vitro translation system using in vitro transcribed mRNA encoding green fluorescent protein (GFP) to evaluate the effects of exposure of GFP mRNA to 0-100 μM of cisplatin, oxaliplatin, or carboplatin. We additionally investigated the interaction between these drugs and mRNA through evaluation of crossing-points during quantitative real-time polymerase chain reactions. In contrast to oxaliplatin or carboplatin, 100 μM cisplatin significantly increased crossing-points by about 3 cycles (P<0.01) and profoundly attenuated translation of GFP mRNA (P<0.05). Oxaliplatin showed a trend to reduce GFP mRNA translation, whereas carboplatin entirely failed to influence it. In conclusion, this study for the very first time documents different effects of platinum cytostatics on mRNA translation and demonstrates mRNA to be a functionally relevant target of at least cisplatin.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Jonas Philipp
authors.initials: JP
authors.lastname: Becker
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address: johanna.weiss@med.uni-heidelberg.de.
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Theile
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; D000077150:Oxaliplatin; D049452:Green Fluorescent Proteins; D016190:Carboplatin; D002945:Cisplatin
keywords: Carboplatin; Cisplatin; DDTC; GFP; IRES; In vitro translation; Oxaliplatin; diethyldithiocarbamate; green fluorescent protein; internal ribosome entry site; mRNA