| 18029019 |
Liu JJ, Galettis P, Farr A, Maharaj L, Samarasinha H, McGechan AC, Baguley BC, Bowen RJ, Berners-Price SJ, McKeage MJ: In vitro antitumour and hepatotoxicity profiles of Au (I) and Ag (I) bidentate pyridyl phosphine complexes and relationships to cellular uptake. J Inorg Biochem. 2008 Feb;102(2):303-10. Epub 2007 Sep 26.
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. |
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