title: Trans-platinum(II) complexes with cyclohexylamine as expectator ligand induce necrosis in tumour cells by inhibiting DNA synthesis and RNA transcription.
abstract: BACKGROUND
  Enhanced removal of cisplatin-DNA adducts has been reported as one of main causes of cell resistance to cisplatin. This particular resistance mechanism may be circumvented by platinum complexes that bind differently to DNA. One line of work is focussed on trans platinum complexes, some of which exhibit antitumour activity similar to or even higher than that of their cis counterparts.
  
  
  METHODS
  We synthesised new trans platinum complexes, trans-[PtCl2(cyclohexylamine)(dimethylamine)] and trans-[PtCl2(OH)2(cyclohexylamine)(dimethylamine)], previously evaluated as cytotoxic agents towards different cancer and normal cell lines. These trans platinum compounds were highly effective against a panel of tumoral cell lines either sensitive to or with acquired resistance to cisplatin.
  
  
  RESULTS
  In the present work we examined the mechanisms induced by these compounds to cause tumour cells toxicity. We have found that these compounds induced a complete blockade at the S phase of the cell cycle inhibiting total mRNA transcription and precluding p53 activation.
  
  
  CONCLUSIONS
  In contrast to other DNA-damaging agents, these compounds do not induce senescence-associated permanent arrest. Furthermore, only a small percentage of these cells enter into apoptosis, with most of the population dying by a necrosis-like mechanism.
authors.affiliation: CNIO, Experimental Therapeutics Program, Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Cepero
authors.forename: B
authors.initials: B
authors.lastname: García-Serrelde
authors.forename: V
authors.initials: V
authors.lastname: Moneo
authors.forename: F
authors.initials: F
authors.lastname: Blanco
authors.forename: A M
authors.initials: AM
authors.lastname: González-Vadillo
authors.forename: A
authors.initials: A
authors.lastname: Alvarez-Valdés
authors.forename: C
authors.initials: C
authors.lastname: Navarro-Ranninger
authors.forename: A
authors.initials: A
authors.lastname: Carnero
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D004247:DNA / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D009336:Necrosis; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D009942:Organometallic Compounds; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; C525438:dichloro(cyclohexylamine)(dimethylamine)platinum(II); C525439:dihydroxo(cyclohexylamine)(dimethylamine)platinum(II); D004247:DNA