TY - JOUR
T1 - Cytotoxicity, mutagenicity, cellular uptake, DNA and glutathione interactions of lipophilic trans-platinum complexes tethered to 1-adamantylamine
AU - Halámiková, Anna
AU - Heringová, Pavla
AU - Kašpárková, Jana
AU - Intini, Francesco P.
AU - Natile, Giovanni
AU - Nemirovski, Alina
AU - Gibson, Dan
AU - Brabec, Viktor
PY - 2008/5
Y1 - 2008/5
N2 - Cytotoxicity and mutagenicity of trans,trans,trans-[PtCl2(CH3COO)2(NH3)(1-adamantylamine)] [trans-adamplatin(IV)] and its reduced analog trans-[PtCl2(NH3)(1-adamantylamine)] [trans-adamplatin(II)] were examined. In addition, the several factors underlying biological effects of these trans-platinum compounds using various biochemical methods were investigated. A notable feature of the growth inhibition studies was the remarkable circumvention of both acquired and intrinsic cisplatin resistance by the two lipophilic trans-compounds. Interestingly, trans-adamplatin(IV) was considerably less mutagenic than cisplatin. Consistent with the lipophilic character of trans-adamplatin complexes, their total accumulation in A2780 cells was considerably greater than that of cisplatin. The results also demonstrate that trans-adamplatin(II) exhibits DNA binding mode markedly different from that of ineffective transplatin. In addition, the reduced deactivation of trans-adamplatin(II) by glutathione seems to be an important determinant of the cytotoxic effects of the complexes tested in the present work. The factors associated with cytotoxic and mutagenic effects of trans-adamplatin complexes in tumor cell lines examined in the present work are likely to play a significant role in the overall antitumor activity of these complexes.
AB - Cytotoxicity and mutagenicity of trans,trans,trans-[PtCl2(CH3COO)2(NH3)(1-adamantylamine)] [trans-adamplatin(IV)] and its reduced analog trans-[PtCl2(NH3)(1-adamantylamine)] [trans-adamplatin(II)] were examined. In addition, the several factors underlying biological effects of these trans-platinum compounds using various biochemical methods were investigated. A notable feature of the growth inhibition studies was the remarkable circumvention of both acquired and intrinsic cisplatin resistance by the two lipophilic trans-compounds. Interestingly, trans-adamplatin(IV) was considerably less mutagenic than cisplatin. Consistent with the lipophilic character of trans-adamplatin complexes, their total accumulation in A2780 cells was considerably greater than that of cisplatin. The results also demonstrate that trans-adamplatin(II) exhibits DNA binding mode markedly different from that of ineffective transplatin. In addition, the reduced deactivation of trans-adamplatin(II) by glutathione seems to be an important determinant of the cytotoxic effects of the complexes tested in the present work. The factors associated with cytotoxic and mutagenic effects of trans-adamplatin complexes in tumor cell lines examined in the present work are likely to play a significant role in the overall antitumor activity of these complexes.
KW - Adamantylamine ligand
KW - Antitumor platinum
KW - Cytotoxicity
KW - DNA binding
KW - Mutagenicity
UR - http://www.scopus.com/inward/record.url?scp=41949095467&partnerID=8YFLogxK
U2 - 10.1016/j.jinorgbio.2007.12.015
DO - 10.1016/j.jinorgbio.2007.12.015
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C2 - 18237783
AN - SCOPUS:41949095467
SN - 0162-0134
VL - 102
SP - 1077
EP - 1089
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
IS - 5-6
ER -
