Intrinsic and acquired forms of resistance against the anticancer ruthenium compound KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A)

The Journal of Pharmacology and Experimental Therapeutics
P HeffeterW Berger

Abstract

KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A) is a metal complex with promising anticancer activity. Since chemoresistance is a major obstacle in chemotherapy, this study investigated the influence of several drug resistance mechanisms on the anticancer activity of KP1019. Here we demonstrate that the cytotoxic effects of KP1019 are neither substantially hampered by overexpression of the drug resistance proteins multidrug resistance-related protein 1, breast cancer resistance protein, and lung resistance protein nor the transferrin receptor and only marginally by the cellular p53 status. In contrast, P-glycoprotein overexpression weakly but significantly (up to 2-fold) reduced KP1019 activity. P-glycoprotein-related resistance was based on reduced intracellular KP1019 accumulation and reversible by known P-glycoprotein modulators. KP1019 dose dependently inhibited ATPase activity of P-glycoprotein with a K(i) of approximately 31 microM. Furthermore, it potently blocked P-glycoprotein-mediated rhodamine 123 efflux under serum-free conditions (EC(50), approximately 8 microM), however, with reduced activity at increased serum concentrations (EC(50) at 10% serum, approximately 35 microM). Moreover, ...Continue Reading

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Citations

Mar 12, 2010·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Petra HeffeterGunda Koellensperger
Mar 10, 2010·Cancer Chemotherapy and Pharmacology·Emmanuel S Antonarakis, Ashkan Emadi
Jun 25, 2013·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Petra HeffeterWalter Berger
Nov 14, 2016·Journal of Inorganic Biochemistry·Sara RojasCarmen R Maldonado
Oct 1, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sarah SpreckelmeyerAngela Casini
Dec 12, 2017·ESMO Open·Thorsten Fuereder, Walter Berger
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Jun 28, 2011·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Caroline BartelBernhard K Keppler
May 30, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Enzo Alessio, Luigi Messori
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Aug 10, 2021·Angewandte Chemie·Sierra C MarkerJustin J Wilson
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Oct 2, 2007·Biochemical Pharmacology·Alla KorynevskaWalter Berger
Apr 3, 2009·Cancer Letters·Tatjana MijatovicWalter Berger

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