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Michael Micksche - One of the best experts on this subject based on the ideXlab platform.
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multidrug Resistance markers p glycoProtein multidrug Resistance Protein 1 and Lung Resistance Protein in non small cell Lung cancer prognostic implications
Journal of Cancer Research and Clinical Oncology, 2005Co-Authors: Walter Berger, Elisabeth Steiner, L Elbling, Ulrike Setinek, Peter Hollaus, Thomas Zidek, Heidi Cantonati, Johannes Attems, Andrea Gsur, Michael MickscheAbstract:The aim of this retrospective study was to comparatively investigate the expression of the three drug-Resistance genes P-glycoProtein (P-gp), multidrug-Resistance Protein 1 (MRP1), and Lung Resistance Protein (LRP), in non-small cell Lung cancer (NSCLC) tissues, and to assess possible associations with clinicopathologic features. Tumor specimens from 126 patients were analyzed by immunohistochemistry and, in selected cases, by reverse transcriptase polymerase chain reaction (RT-PCR), and data were statistically analyzed by SPSS. The mean expression levels of tumor tissues in the case of P-gp and LRP did not exceed the one of normal epithelia, while MRP1 was significantly enhanced in NSCLC. A weak association was observed between higher grading and P-glycoProtein expression ( p <0.08) as well as lower grading and MRP1 expression in the case of adenocarcinoma ( p <0.05). MRP1 levels were highest in TNM stage I and declined with advanced stage ( p <0.03). A significant association was found between high MRP1 levels and longer overall survival ( N =115, p <0.04), which was highly significant in the patient group never treated with chemotherapy ( N =77; p <0.007). P-gp expression was enhanced in those patients who had received chemotherapy before surgery ( p <0.05). Our data point towards a major role of MRP1 in the intrinsic treatment Resistance of NSCLC and suggest, in addition, a significant activation of P-gp expression during chemotherapy.
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intrinsic and acquired forms of Resistance against the anticancer ruthenium compound kp1019 indazolium trans tetrachlorobis 1h indazole ruthenate iii ffc14a
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Petra Heffeter, Martin Pongratz, Elisabeth Steiner, Michael A Jakupec, L Elbling, Wilfried Korner, Florian Sevelda, Peter Chiba, Brigitte Marian, Michael MickscheAbstract:KP1019 \[indazolium trans -[tetrachlorobis(1 H -indazole)ruthenate (III)\] (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 ∼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.
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intrinsic and acquired forms of Resistance against the anticancer ruthenium compound kp1019 indazolium trans tetrachlorobis 1h indazole ruthenate iii ffc14a
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Petra Heffeter, Martin Pongratz, Elisabeth Steiner, Michael A Jakupec, L Elbling, Wilfried Korner, Florian Sevelda, Peter Chiba, Brigitte Marian, Michael MickscheAbstract: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, 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 approximately 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.
Petra Heffeter - One of the best experts on this subject based on the ideXlab platform.
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intrinsic and acquired forms of Resistance against the anticancer ruthenium compound kp1019 indazolium trans tetrachlorobis 1h indazole ruthenate iii ffc14a
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Petra Heffeter, Martin Pongratz, Elisabeth Steiner, Michael A Jakupec, L Elbling, Wilfried Korner, Florian Sevelda, Peter Chiba, Brigitte Marian, Michael MickscheAbstract:KP1019 \[indazolium trans -[tetrachlorobis(1 H -indazole)ruthenate (III)\] (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 ∼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.
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intrinsic and acquired forms of Resistance against the anticancer ruthenium compound kp1019 indazolium trans tetrachlorobis 1h indazole ruthenate iii ffc14a
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Petra Heffeter, Martin Pongratz, Elisabeth Steiner, Michael A Jakupec, L Elbling, Wilfried Korner, Florian Sevelda, Peter Chiba, Brigitte Marian, Michael MickscheAbstract: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, 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 approximately 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.
Elisabeth Steiner - One of the best experts on this subject based on the ideXlab platform.
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multidrug Resistance markers p glycoProtein multidrug Resistance Protein 1 and Lung Resistance Protein in non small cell Lung cancer prognostic implications
Journal of Cancer Research and Clinical Oncology, 2005Co-Authors: Walter Berger, Elisabeth Steiner, L Elbling, Ulrike Setinek, Peter Hollaus, Thomas Zidek, Heidi Cantonati, Johannes Attems, Andrea Gsur, Michael MickscheAbstract:The aim of this retrospective study was to comparatively investigate the expression of the three drug-Resistance genes P-glycoProtein (P-gp), multidrug-Resistance Protein 1 (MRP1), and Lung Resistance Protein (LRP), in non-small cell Lung cancer (NSCLC) tissues, and to assess possible associations with clinicopathologic features. Tumor specimens from 126 patients were analyzed by immunohistochemistry and, in selected cases, by reverse transcriptase polymerase chain reaction (RT-PCR), and data were statistically analyzed by SPSS. The mean expression levels of tumor tissues in the case of P-gp and LRP did not exceed the one of normal epithelia, while MRP1 was significantly enhanced in NSCLC. A weak association was observed between higher grading and P-glycoProtein expression ( p <0.08) as well as lower grading and MRP1 expression in the case of adenocarcinoma ( p <0.05). MRP1 levels were highest in TNM stage I and declined with advanced stage ( p <0.03). A significant association was found between high MRP1 levels and longer overall survival ( N =115, p <0.04), which was highly significant in the patient group never treated with chemotherapy ( N =77; p <0.007). P-gp expression was enhanced in those patients who had received chemotherapy before surgery ( p <0.05). Our data point towards a major role of MRP1 in the intrinsic treatment Resistance of NSCLC and suggest, in addition, a significant activation of P-gp expression during chemotherapy.
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intrinsic and acquired forms of Resistance against the anticancer ruthenium compound kp1019 indazolium trans tetrachlorobis 1h indazole ruthenate iii ffc14a
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Petra Heffeter, Martin Pongratz, Elisabeth Steiner, Michael A Jakupec, L Elbling, Wilfried Korner, Florian Sevelda, Peter Chiba, Brigitte Marian, Michael MickscheAbstract:KP1019 \[indazolium trans -[tetrachlorobis(1 H -indazole)ruthenate (III)\] (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 ∼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.
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intrinsic and acquired forms of Resistance against the anticancer ruthenium compound kp1019 indazolium trans tetrachlorobis 1h indazole ruthenate iii ffc14a
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Petra Heffeter, Martin Pongratz, Elisabeth Steiner, Michael A Jakupec, L Elbling, Wilfried Korner, Florian Sevelda, Peter Chiba, Brigitte Marian, Michael MickscheAbstract: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, 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 approximately 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.
L Elbling - One of the best experts on this subject based on the ideXlab platform.
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multidrug Resistance markers p glycoProtein multidrug Resistance Protein 1 and Lung Resistance Protein in non small cell Lung cancer prognostic implications
Journal of Cancer Research and Clinical Oncology, 2005Co-Authors: Walter Berger, Elisabeth Steiner, L Elbling, Ulrike Setinek, Peter Hollaus, Thomas Zidek, Heidi Cantonati, Johannes Attems, Andrea Gsur, Michael MickscheAbstract:The aim of this retrospective study was to comparatively investigate the expression of the three drug-Resistance genes P-glycoProtein (P-gp), multidrug-Resistance Protein 1 (MRP1), and Lung Resistance Protein (LRP), in non-small cell Lung cancer (NSCLC) tissues, and to assess possible associations with clinicopathologic features. Tumor specimens from 126 patients were analyzed by immunohistochemistry and, in selected cases, by reverse transcriptase polymerase chain reaction (RT-PCR), and data were statistically analyzed by SPSS. The mean expression levels of tumor tissues in the case of P-gp and LRP did not exceed the one of normal epithelia, while MRP1 was significantly enhanced in NSCLC. A weak association was observed between higher grading and P-glycoProtein expression ( p <0.08) as well as lower grading and MRP1 expression in the case of adenocarcinoma ( p <0.05). MRP1 levels were highest in TNM stage I and declined with advanced stage ( p <0.03). A significant association was found between high MRP1 levels and longer overall survival ( N =115, p <0.04), which was highly significant in the patient group never treated with chemotherapy ( N =77; p <0.007). P-gp expression was enhanced in those patients who had received chemotherapy before surgery ( p <0.05). Our data point towards a major role of MRP1 in the intrinsic treatment Resistance of NSCLC and suggest, in addition, a significant activation of P-gp expression during chemotherapy.
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intrinsic and acquired forms of Resistance against the anticancer ruthenium compound kp1019 indazolium trans tetrachlorobis 1h indazole ruthenate iii ffc14a
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Petra Heffeter, Martin Pongratz, Elisabeth Steiner, Michael A Jakupec, L Elbling, Wilfried Korner, Florian Sevelda, Peter Chiba, Brigitte Marian, Michael MickscheAbstract:KP1019 \[indazolium trans -[tetrachlorobis(1 H -indazole)ruthenate (III)\] (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 ∼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.
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intrinsic and acquired forms of Resistance against the anticancer ruthenium compound kp1019 indazolium trans tetrachlorobis 1h indazole ruthenate iii ffc14a
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Petra Heffeter, Martin Pongratz, Elisabeth Steiner, Michael A Jakupec, L Elbling, Wilfried Korner, Florian Sevelda, Peter Chiba, Brigitte Marian, Michael MickscheAbstract: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, 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 approximately 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.
Michael A Jakupec - One of the best experts on this subject based on the ideXlab platform.
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intrinsic and acquired forms of Resistance against the anticancer ruthenium compound kp1019 indazolium trans tetrachlorobis 1h indazole ruthenate iii ffc14a
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Petra Heffeter, Martin Pongratz, Elisabeth Steiner, Michael A Jakupec, L Elbling, Wilfried Korner, Florian Sevelda, Peter Chiba, Brigitte Marian, Michael MickscheAbstract:KP1019 \[indazolium trans -[tetrachlorobis(1 H -indazole)ruthenate (III)\] (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 ∼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.
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intrinsic and acquired forms of Resistance against the anticancer ruthenium compound kp1019 indazolium trans tetrachlorobis 1h indazole ruthenate iii ffc14a
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Petra Heffeter, Martin Pongratz, Elisabeth Steiner, Michael A Jakupec, L Elbling, Wilfried Korner, Florian Sevelda, Peter Chiba, Brigitte Marian, Michael MickscheAbstract: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, 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 approximately 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.
