title: Cytotoxic activity of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide is underlain by DNA interchain cross-linking.
abstract: Currently, chemical bifunctional cross-linkers are regarded as promising therapeutic agents capable of affecting cell metabolism. Depending on the nature of the active groups and on the length of their mediating spacer, these cross-linkers have been shown to influence mitochondrial functions, the cell cycle and cell death. The current study was aimed to assay cellular effects of a cross-linker with 'zero'-length spacer, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). When added to cultures of transformed cells, EDC induced a G2/M blockade followed by cell death. Analysis of the molecular targets revealed that alteration of the cell cycle was caused by EDC-induced interchain cross-linking within double-stranded DNA. Administration of EDC to animals with experimental tumors increased their life span. The analysis of tumor cells from EDC-treated mice showed up-regulation of p21/WAF1, disturbance of tumor cell cytokinesis and, hence, cell death. Thus, both in vitro and in vivo, EDC exhibits cytotoxic activity, which may be of potential therapeutic use.
authors.affiliation: Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, ul. Institutskaya 3, Pushchino, Moscow Region 142290, Russia.
authors.forename: A B
authors.initials: AB
authors.lastname: Moshnikova
authors.forename: V N
authors.initials: VN
authors.lastname: Afanasyev
authors.forename: O V
authors.initials: OV
authors.lastname: Proussakova
authors.forename: S
authors.initials: S
authors.lastname: Chernyshov
authors.forename: V
authors.initials: V
authors.lastname: Gogvadze
authors.forename: I P
authors.initials: IP
authors.lastname: Beletsky
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D002522:Chlorocebus aethiops; D003432:Cross-Linking Reagents; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D048749:Cytokinesis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005022:Ethyldimethylaminopropyl Carbodiimide / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA
chemical_list: D003432:Cross-Linking Reagents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005022:Ethyldimethylaminopropyl Carbodiimide