2005
Kozubík, Alois; Horváth, Viktor; Svihálková-Sindlerová, Lenka; Soucek, Karel; Hofmanová, Jirina; Sova, Petr; Kroutil, Ales; Zák, Frantisek; Mistr, Adolf; Turánek, Jaroslav
In: Biochemical pharmacology, vol. 69, no. 3, pp. 373–383, 2005, ISSN: 0006-2952, (Place: England).
Abstract | Links | BibTeX | Tags: Amantadine/*analogs & derivatives/*pharmacology, Antineoplastic Agents/*pharmacology, Cell Cycle/drug effects, Cell Line, Cell Proliferation/drug effects, Cisplatin/*pharmacology, DNA Fragmentation/drug effects, Drug resistance, Female, Humans, Neoplasm, Organoplatinum Compounds/*pharmacology, Ovarian Neoplasms/*drug therapy/pathology, Poly(ADP-ribose) Polymerases/analysis, Tumor, Tumor Suppressor Protein p53/analysis
@article{kozubik_high_2005,
title = {High effectiveness of platinum(IV) complex with adamantylamine in overcoming resistance to cisplatin and suppressing proliferation of ovarian cancer cells in vitro.},
author = {Alois Kozubík and Viktor Horváth and Lenka Svihálková-Sindlerová and Karel Soucek and Jirina Hofmanová and Petr Sova and Ales Kroutil and Frantisek Zák and Adolf Mistr and Jaroslav Turánek},
doi = {10.1016/j.bcp.2004.09.005},
issn = {0006-2952},
year = {2005},
date = {2005-02-01},
journal = {Biochemical pharmacology},
volume = {69},
number = {3},
pages = {373–383},
abstract = {[(OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)], coded as LA-12, is an octahedral platinum(IV) complex containing a bulky hydrophobic ligand - adamantylamine. The use of bulky hydrophobic amines as non-leaving ligands, may increase uptake of the compound by the cancer cells. Therefore, the effects of LA-12 on sensitive (A2780) and cisplatin resistant (A2780cis) ovarian cancer cell lines were investigated and compared to those of cisplatin. IC(50) and IC(90) concentrations of LA-12 were 6- (A2780) or 18-fold (A2780cis) lower than those for cisplatin (MTT assay). Equitoxic concentrations (IC(50) or IC(90)) of both compounds caused a significant and similar time- and dose-dependent inhibition of cell proliferation and an increase in the number of floating cells which corresponded to the decrease of total cell viability. A different type and dynamics of cell cycle perturbation after cisplatin and LA-12 treatment were detected. Exposure to LA-12 resulted in transient accumulation of A2780 and A2780cis cells in S phase, while cisplatin caused G(2)/M arrest in sensitive and S phase arrest in resistant cells. A relatively low rate of apoptosis after exposure to IC(50) or IC(90) of both complexes was observed, markedly higher in resistant A2780cis cells. Western blot analysis indicated a concentration-dependent p53 level increase in both lines (higher after cisplatin treatment). PARP cleavage was observed only in A2780cis cells. In conclusion, LA-12 was found to be significantly more efficient than cisplatin, and it was able to overcome the acquired cisplatin resistance (showing resistance factor 2.84-fold lower than those for cisplatin). In spite of the low rate of apoptosis, LA-12 caused increase of p53 level and cell cycle perturbations in the ovarian cancer cell lines studied.},
note = {Place: England},
keywords = {Amantadine/*analogs & derivatives/*pharmacology, Antineoplastic Agents/*pharmacology, Cell Cycle/drug effects, Cell Line, Cell Proliferation/drug effects, Cisplatin/*pharmacology, DNA Fragmentation/drug effects, Drug resistance, Female, Humans, Neoplasm, Organoplatinum Compounds/*pharmacology, Ovarian Neoplasms/*drug therapy/pathology, Poly(ADP-ribose) Polymerases/analysis, Tumor, Tumor Suppressor Protein p53/analysis},
pubstate = {published},
tppubtype = {article}
}
[(OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)], coded as LA-12, is an octahedral platinum(IV) complex containing a bulky hydrophobic ligand - adamantylamine. The use of bulky hydrophobic amines as non-leaving ligands, may increase uptake of the compound by the cancer cells. Therefore, the effects of LA-12 on sensitive (A2780) and cisplatin resistant (A2780cis) ovarian cancer cell lines were investigated and compared to those of cisplatin. IC(50) and IC(90) concentrations of LA-12 were 6- (A2780) or 18-fold (A2780cis) lower than those for cisplatin (MTT assay). Equitoxic concentrations (IC(50) or IC(90)) of both compounds caused a significant and similar time- and dose-dependent inhibition of cell proliferation and an increase in the number of floating cells which corresponded to the decrease of total cell viability. A different type and dynamics of cell cycle perturbation after cisplatin and LA-12 treatment were detected. Exposure to LA-12 resulted in transient accumulation of A2780 and A2780cis cells in S phase, while cisplatin caused G(2)/M arrest in sensitive and S phase arrest in resistant cells. A relatively low rate of apoptosis after exposure to IC(50) or IC(90) of both complexes was observed, markedly higher in resistant A2780cis cells. Western blot analysis indicated a concentration-dependent p53 level increase in both lines (higher after cisplatin treatment). PARP cleavage was observed only in A2780cis cells. In conclusion, LA-12 was found to be significantly more efficient than cisplatin, and it was able to overcome the acquired cisplatin resistance (showing resistance factor 2.84-fold lower than those for cisplatin). In spite of the low rate of apoptosis, LA-12 caused increase of p53 level and cell cycle perturbations in the ovarian cancer cell lines studied.