Studies of the mechanism of action of platinum(II) complexes with potent cytotoxicity in human cancer cells.
We have examined the biological activity of 12 platinum(II)-based DNA intercalators of the type [Pt(I(L))(A(L))](2+), where I(L) is an intercalating ligand (1,10-phenanthroline or a methylated derivative) and A(L) is an ancillary ligand (diaminocyclohexane, diphenylethylenediamine or 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine). The chiral compounds (1-9) and the racemic compounds (10-12) were tested against a panel of human cancer cell lines, with a number of complexes displaying activity significantly greater than that of cisplatin (up to 100-fold increase in activity in the A-427 cell line). The activity of the complexes containing diphenylethylenediamine (8 and 9) and 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine (10-12) was significantly lower compared to the complexes containing diaminocyclohexane (1-7). Further in vitro testing, such as DNA unwinding, competition assays, and DNase 1 footprinting, was conducted on the most active compound (5) and its enantiomer (6) to provide information about the mechanism of action. These complexes display activity in cisplatin resistant cell lines, have higher cellular uptake than cisplatin, and do not activate caspase-3 as cisplatin does, indicating that these complexes exhibit a different mechanism of action.
Krause-Heuer
Anwen M
AM
School of Biomedical and Health Sciences, University of Western Sydney, Penrith South DC, NSW, Australia.
Grünert
Renate
R
Kühne
Sybill
S
Buczkowska
Magdalena
M
Wheate
Nial J
NJ
Le Pevelen
Delphine D
DD
Boag
Leanne R
LR
Fisher
Dianne M
DM
Kasparkova
Jana
J
Malina
Jaroslav
J
Bednarski
Patrick J
PJ
Brabec
Viktor
V
Aldrich-Wright
Janice R
JR
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D001692:Biological Transport; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004278:DNA, Superhelical / Q000737:chemistry / Q000235:genetics; D003850:Deoxyribonuclease I / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010984:Platinum / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013696:Temperature
D000970:Antineoplastic Agents; D004278:DNA, Superhelical; D008024:Ligands; D009942:Organometallic Compounds; D010984:Platinum; D003850:Deoxyribonuclease I; D053148:Caspase 3; D002945:Cisplatin