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.
(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.
Dietrich
Andrea
A
Department of Hematology/Oncology, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany. andrea.dietrich@medizin.uni-halle.de
Mueller
Thomas
T
Paschke
Reinhard
R
Kalinowski
Bernd
B
Behlendorf
Timo
T
Reipsch
Franziska
F
Fruehauf
Angelika
A
Schmoll
Hans-Joachim
HJ
Kloft
Charlotte
C
Voigt
Wieland
W
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
D009944:Organoplatinum Compounds; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D002945:Cisplatin