PT - JOURNAL ARTICLE AU - P. Heffeter AU - M. Pongratz AU - E. Steiner AU - P. Chiba AU - M. A. Jakupec AU - L. Elbling AU - B. Marian AU - W. Körner AU - F. Sevelda AU - M. Micksche AU - B. K. Keppler AU - W. Berger TI - Intrinsic and Acquired Forms of Resistance against the Anticancer Ruthenium Compound KP1019 [Indazolium <em>trans</em>-[tetrachlorobis(1<em>H</em>-indazole)ruthenate (III)] (FFC14A) AID - 10.1124/jpet.104.073395 DP - 2005 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 281--289 VI - 312 IP - 1 4099 - http://jpet.aspetjournals.org/content/312/1/281.short 4100 - http://jpet.aspetjournals.org/content/312/1/281.full SO - J Pharmacol Exp Ther2005 Jan 01; 312 AB - 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 Ki of ∼31 μM. Furthermore, it potently blocked P-glycoprotein-mediated rhodamine 123 efflux under serum-free conditions (EC50, ∼8 μM), however, with reduced activity at increased serum concentrations (EC50 at 10% serum, ∼35 μM). 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. The American Society for Pharmacology and Experimental Therapeutics