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First published on August 26, 2004; DOI: 10.1124/jpet.104.073395

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*Substance via MeSH


Received for publication June 28, 2004.
Revised August 25, 2004.
Accepted for publication August 26, 2004.

Intrinsic and Acquired Forms of Resistance Against the Anticancer Ruthenium Compound KP1019 (FFC14A)

Petra Heffeter 1, Martina Pongratz 2, Elisabeth Steiner 1, Peter Chiba 3, Michael A Jakupec 4, Leonilla Elbling 1, Brigitte Marian 1, Winfried Korner 5, Florian Sevelda 1, Michael Micksche 1, Bernhard K Keppler 4, Walter Berger 1*

1 Institute of Cancer Research, Medical University Vienna 2 Insitute of Inorganic Chemistry, Vienna University 3 Institute of Medical Chemistry, Medical University Vienna 4 Institute of Inorganic Chemistry, University of Vienna 5 Institute for Geological Sciences, University of Vienna

* Address correspondence to: E-mail: walter.berger{at}meduniwien.ac.at

Abstract

Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (KP1019; 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 MRP1, BCRP, and LRP 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 Ki of ~31µM. Furthermore, it potently blocked P-glycoprotein-mediated rhodamine 123 efflux under serum-free conditions (EC50 ~8µM), however, with reduced activity at increased serum concentrations (at 10% serum EC50 ~35µM). Moreover, P-glycoprotein-mediated daunomycin resistance could only be marginally restored by KP1019 in serum-containing medium, also indicating an influence of serum proteins on the interaction between KP1019 and P-glycoprotein. Acquired KP1019 resistance was investigated by selecting KB-3-1 cells against KP1019 for more than one year. Only an ~2-fold KP1019 resistance could be induced which unexpectedly was not due to overexpression of P-glycoprotein or other efflux pumps. Accordingly, KP1019-resistant cells did not display reduced drug accumulation. Their unique cross-resistance pattern confirmed an ABC-transporter-independent resistance phenotype. Summarizing, the likeliness of acquiring insensitivity to KP1019 during therapy is expected to be low and resistance should not be based on overexpression of drug efflux transporters.


Key words: KP1019, MRP, P-glycoprotein, multidrug resistance, ruthenium, transferrin receptor




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