Intrinsic and acquired forms of resistance against the anticancer ruthenium compound KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A)
- Author(s)
- Petra Heffeter, Martina Pongratz, Elisabeth Steiner, Peter Chiba, Michael Jakupec, Leonilla Elbling, Brigitte Marian, Wilfried Körner, Florian Sevelda, Michael Micksche, Bernhard Keppler, Walter 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 dependency inhibited ATPase activity of P-glycoprotein with a K1 of ~31 mikroM. Furthermore, it potently blocked P-glycoprotein-mediated rhodamine 123 efflux under serum-free conditions (EC50, ~8 mikroM), however, with reduced activity at increased serum concentrations (EC50 at 10% serum, ~35 mikroM). 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 1 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. In summary, 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.
- Organisation(s)
- Department of Inorganic Chemistry
- External organisation(s)
- Medizinische Universität Wien
- Journal
- Journal of Pharmacology and Experimental Therapeutics
- Volume
- 312
- Pages
- 281-289
- No. of pages
- 9
- ISSN
- 0022-3565
- DOI
- https://doi.org/10.1124/jpet.104.073395
- Publication date
- 2005
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301904 Cancer research
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/c8f2f429-5bad-4e77-879b-aacac4d2cd06