In vitro antitumour and hepatotoxicity profiles of Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to cellular uptake

• Published in: Journal of inorganic biochemistry Vol. 102; no. 2; pp. 303 - 310
• Main Authors: Liu, Johnson J., Galettis, Peter, Farr, Alistair, Maharaj, Lenushka, Samarasinha, Hasitha, McGechan, Adam C., Baguley, Bruce C., Bowen, Richard J., Berners-Price, Susan J., McKeage, Mark J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-02-2008
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Antitumour activity; Cell Line, Tumor; Cisplatin - pharmacology; Gold(I) and silver(I) phosphines; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Male; Organogold Compounds - chemistry; Organogold Compounds - pharmacology; Organogold Compounds - toxicity; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Organometallic Compounds - toxicity; Ovarian cancer cell-lines; Phosphines - chemistry; Phosphines - pharmacology; Phosphines - toxicity; Rats; Rats, Wistar; Silver - chemistry; Silver - pharmacology; Silver - toxicity; Ovarian cancer cell-lines; Antitumour activity; Gold(I) and silver(I) phosphines; Hepatocytes
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2007.09.003

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.