title: In vitro antitumour and hepatotoxicity profiles of Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to cellular uptake.
abstract: 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.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland 1142, New Zealand.
authors.forename: Johnson J
authors.initials: JJ
authors.lastname: Liu
authors.forename: Peter
authors.initials: P
authors.lastname: Galettis
authors.forename: Alistair
authors.initials: A
authors.lastname: Farr
authors.forename: Lenushka
authors.initials: L
authors.lastname: Maharaj
authors.forename: Hasitha
authors.initials: H
authors.lastname: Samarasinha
authors.forename: Adam C
authors.initials: AC
authors.lastname: McGechan
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Baguley
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bowen
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Berners-Price
authors.forename: Mark J
authors.initials: MJ
authors.lastname: McKeage
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D050607:Organogold Compounds; D009942:Organometallic Compounds; D010720:Phosphines; D012834:Silver; D002945:Cisplatin