title: 2-(4-(Tetrahydro-2H-pyran-2-yloxy)-undecyl)-propane-1,3-diamminedichloroplatinum(II): a novel platinum compound that overcomes cisplatin resistance and induces apoptosis by mechanisms different from that of cisplatin.
abstract: (4-(Tetrahydro-2H-pyran-2-yloxy)R1)R2-diamminedichloroplatinum(II) complexes (1-12) consisting of CDDP linked to THP via aliphatic CH2-spacers were tested in two TGCT cell lines. The most promising compound, 2-(4-(tetrahydro-2H-pyran-2-yloxy)-undecyl)-propane-1,3-diamminedichloroplatinum(II) (12), completely overcame CDDP resistance of 1411HP cells, correlating with increased and accelerated cellular platinum uptake and much faster initiation of apoptotic cell kill. At equitoxic IC90 concentrations, 12 induced accelerated DNA fragmentation and caspase -3 and PARP cleavages. In contrast, DNA platination rate was much lower as compared to CDDP and no upregulation of p53 as well as no initiation of cell cycle arrest were observed. Apoptosis induction by 12 could not be inhibited by pretreatment with caspase-specific inhibitor Z-VAD-Fmk and was accompanied by strong calcium release and generation of reactive oxygen species. To summarize, 12 overcomes CDDP resistance and induces programmed cell death with molecular features different from CDDP, suggesting that both drugs induce apoptosis through different initial pathways.
authors.affiliation: Department of Hematology/Oncology, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany. andrea.dietrich@medizin.uni-halle.de
authors.forename: Andrea
authors.initials: A
authors.lastname: Dietrich
authors.forename: Thomas
authors.initials: T
authors.lastname: Mueller
authors.forename: Reinhard
authors.initials: R
authors.lastname: Paschke
authors.forename: Bernd
authors.initials: B
authors.lastname: Kalinowski
authors.forename: Timo
authors.initials: T
authors.lastname: Behlendorf
authors.forename: Franziska
authors.initials: F
authors.lastname: Reipsch
authors.forename: Angelika
authors.initials: A
authors.lastname: Fruehauf
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schmoll
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kloft
authors.forename: Wieland
authors.initials: W
authors.lastname: Voigt
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology*; D053938:DNA Fragmentation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D009944:Organoplatinum Compounds; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D002945:Cisplatin