title: Transplatin enhances effect of cisplatin on both single DNA molecules and live tumor cells.
abstract: Cisplatin is the main platinum antitumor drug applied in clinical settings. However, its trans isomer, transplatin, is known to have an ineffective antitumor activity. Despite intensive studies in this field, the structural and biophysical properties of DNA molecules reacting with these two platinum complexes have not been fully elucidated. In the present study, we observed that transplatin made efficient cross-linking of DNA in the vicinity of cisplatin adducts. High-resolution atomic force microscopy studies revealed that the transplatin-induced cross-linkings of nucleotides flanking cisplatin adducts were characterized by kinked-loop structures with rod-like shapes of nanometer scales (∼10-60nm). The results were further confirmed by denaturing gel electrophoresis and single-molecule experiment using magnetic tweezers. In vivo studies revealed that transplatin and cisplatin co-treatment could induce a considerable amount of kinked loops with smaller sizes (∼15nm) in cellular DNA. Furthermore, compared with cisplatin treatment alone, the co-treatment resulted in enhanced cytotoxicity, increased amount of interstrand cross-links, and cell lesions more reluctant to cellular repair system. The results of the present study provide a new clue for understanding the stepwise reactions of DNA with platinum drugs and might serve as a basis for the development of a new antitumor strategy.
authors.affiliation: Key Laboratory of Soft Matter Physics, Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Yu-Ru
authors.initials: YR
authors.lastname: Liu
authors.forename: Chao
authors.initials: C
authors.lastname: Ji
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Zhang
authors.forename: Shuo-Xing
authors.initials: SX
authors.lastname: Dou
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.forename: Wei-Chi
authors.initials: WC
authors.lastname: Wang
authors.forename: Peng-Ye
authors.initials: PY
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D018736:DNA Adducts / Q000378:metabolism* / Q000648:ultrastructure*; D004357:Drug Synergism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D009690:Nucleic Acid Conformation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; C034697:transplatin; D002945:Cisplatin
keywords: Cisplatin; Cytotoxicity; Kinked-loop structure; Single DNA molecule; Transplatin; Tumor cell