In vitro antitumour and hepatotoxicity profiles of Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to cellular uptake.
In this study we characterised the in vitro antitumour and hepatotoxicity profiles of a series of Au(I) and Ag(I) bidentate phenyl and pyridyl complexes in a panel of cisplatin-resistant human ovarian cancer cell-lines, and in isolated rat hepatocytes. The gold and silver compounds overcame cisplatin-resistance in the CH1-cisR, 41M-cisR and SKOV-3 cell-lines, and showed cytotoxic potencies strongly correlated with their lipophilicity. Complexes with phenyl or 2-pyridyl ligands had high antitumour and hepatotoxic potency and low selectivity between different cell-lines. Their cytotoxicity profiles were similar to classic mitochondrial poisons and an example of this type of compound was shown to accumulate preferentially in the mitochondria of cancer cells in a manner that depended upon the mitochondrial membrane potential. In contrast, complexes with 3- or 4-pyridyl ligands had low antitumour and hepatotoxic potency and cytotoxicity profiles similar to 2-deoxy-D-glucose. In addition, they showed high selectivity between different cell-lines that was not attributable to variation in uptake in different cell-types. The in vitro hepatotoxic potency of the series of gold and silver compounds varied by over 61-fold and was closely related to their lipophilicity and hepatocyte uptake. In conclusion, Au(I) and Ag(I) bidendate pyridyl phosphine complexes demonstrate activity against cisplatin-resistant human cancer cells and in vitro cytotoxicity that strongly depends upon their lipophilicity.
Liu
Johnson J
JJ
Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland 1142, New Zealand.
Galettis
Peter
P
Farr
Alistair
A
Maharaj
Lenushka
L
Samarasinha
Hasitha
H
McGechan
Adam C
AC
Baguley
Bruce C
BC
Bowen
Richard J
RJ
Berners-Price
Susan J
SJ
McKeage
Mark J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D050607:Organogold Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010720:Phosphines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012834:Silver / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
D000970:Antineoplastic Agents; D050607:Organogold Compounds; D009942:Organometallic Compounds; D010720:Phosphines; D012834:Silver; D002945:Cisplatin