The Experts below are selected from a list of 6261 Experts worldwide ranked by ideXlab platform
Petra Heffeter - One of the best experts on this subject based on the ideXlab platform.
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nanoformulation improves activity of the pre clinical anticancer Ruthenium complex kp1019
Journal of Biomedical Nanotechnology, 2014Co-Authors: Petra Heffeter, Tetyana Konstantinova, Wilfried Korner, Bernhard K Keppler, Christian R Kowol, Anna Riabtseva, Y Senkiv, U Jungwith, Nataliya Mitina, I B YanchukAbstract:: Ruthenium anticancer drugs belong to the most promising non-platinum anticancer metal Compounds in clinical evaluation. However, although the clinical results are promising regarding both activity and very low adverse effects, the clinical application is currently hampered by the limited solubility and stability of the drug in aqueous solution. Here, we present a new nanoparticle formulation based on polymer-based micelles loaded with the anticancer lead Ruthenium Compound KP1019. Nanoprepared KP1019 was characterised by enhanced stability in aqueous solutions. Moreover, the nanoparticle formulation facilitated cellular accumulation of KP1019 (determined by ICP-MS measurements) resulting in significantly lowered IC50 values. With regard to the mode of action, increased cell cycle arrest in G2/M phase (PI-staining), DNA damage (Comet assay) as well as enhanced levels of apoptotic cell death (caspase 7 and PARP cleavage) were found in HCT116 cells treated with the new nanoformulation of KP1019. Summarizing, we present for the first time evidence that nanoformulation is a feasible strategy for improving the stability as well as activity of experimental anticancer Ruthenium Compounds.
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poly lactic acid nanoparticles of the lead anticancer Ruthenium Compound kp1019 and its surfactant mediated activation
Dalton Transactions, 2014Co-Authors: Britta Fischer, Petra Heffeter, Kushtrim Kryeziu, Samuel M Meier, Christian R Kowol, Walter Berger, Lars Gille, Bernhard K KepplerAbstract:Nanoparticle formulations offer besides the advantage of passive drug targeting also the opportunity to increase the stability of drugs. KP1019 is a lead Ruthenium(III) Compound which has been successfully tested in a clinical phase I trial. However, it is characterized by low stability in aqueous solution especially at physiological pH. To overcome this limitation, poly(lactic acid) (PLA) nanoparticles of KP1019 with two different surfactants (Pluronic F68 and Tween 80) were prepared by a single oil-in-water (o/w) emulsion. Cytotoxicity measurements comparing different aged Tween 80 nanoparticles revealed that the color change from brown to green was associated with an up to 20 fold increased activity compared to “free” KP1019. Further investigations suggested that this is based on the formation of enhanced intracellular reactive oxygen species levels. Additional studies revealed that the origin of the green color is a reaction between KP1019 and Tween 80. Kinetic studies of this reaction mixture using UV-Vis, ESI-MS and ESR spectroscopy indicated on the one hand a coordination of Tween 80 to KP1019, and on the other hand, the color change was found to correlate with a reduction of the Ru(III) center by the surfactant. Together, the results provide a first experimental approach to stabilize a biologically active Ru(II) species of KP1019 in aqueous solution, which probably can be also used to selectively generate this activated species in the tumor tissue via delivery of KP1019 using Tween 80 nanoparticles.
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the Ruthenium Compound kp1339 potentiates the anticancer activity of sorafenib in vitro and in vivo
European Journal of Cancer, 2013Co-Authors: Petra Heffeter, Wilfried Korner, Bernhard K Keppler, Kushtrim Kryeziu, Ute Jungwirth, Bihter Atil, Diana Groza, Gunda Koellensperger, Thomas Mohr, Walter BergerAbstract:KP1339 is a promising Ruthenium-based anticancer Compound in early clinical development. This study aimed to test the effects of KP1339 on the in vitro and in vivo activity of the multi-kinase inhibitor sorafenib, the current standard first-line therapy for advanced hepatoma. Anticancer activity of the parental Compounds as compared to the drug combination was tested against a panel of cancer cell lines with a focus on hepatoma. Combination of KP1339 with sorafenib induced in the majority of all cases distinctly synergistic effects, comprising both sorafenib-resistant as well as sorafenib-responsive cell models. Several mechanisms were found to underlie these multifaceted synergistic activities. Firstly, co-exposure induced significantly enhanced accumulation levels of both drugs resulting in enhanced apoptosis induction. Secondly, sorafenib blocked KP1339-mediated activation of P38 signalling representing a protective response against the Ruthenium drug. In addition, sorafenib treatment also abrogated KP1339-induced G2/M arrest but resulted in check point-independent DNA-synthesis block and a complete loss of the mitotic cell populations. The activity of the KP1339/sorafenib combination was evaluated in the Hep3B hepatoma xenograft. KP1339 monotherapy led to a 2.4-fold increase in life span and, thus, was superior to sorafenib, which induced a 1.9-fold prolonged survival. The combined therapy further enhanced the mean survival by 3.9-fold. Synergistic activity was also observed in the VM-1 melanoma xenograft harbouring an activating braf mutation. Together, our data indicate that the combination of KP1339 with sorafenib displays promising activity in vitro and in vivo especially against human hepatoma models.
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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.
Wilfried Korner - One of the best experts on this subject based on the ideXlab platform.
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nanoformulation improves activity of the pre clinical anticancer Ruthenium complex kp1019
Journal of Biomedical Nanotechnology, 2014Co-Authors: Petra Heffeter, Tetyana Konstantinova, Wilfried Korner, Bernhard K Keppler, Christian R Kowol, Anna Riabtseva, Y Senkiv, U Jungwith, Nataliya Mitina, I B YanchukAbstract:: Ruthenium anticancer drugs belong to the most promising non-platinum anticancer metal Compounds in clinical evaluation. However, although the clinical results are promising regarding both activity and very low adverse effects, the clinical application is currently hampered by the limited solubility and stability of the drug in aqueous solution. Here, we present a new nanoparticle formulation based on polymer-based micelles loaded with the anticancer lead Ruthenium Compound KP1019. Nanoprepared KP1019 was characterised by enhanced stability in aqueous solutions. Moreover, the nanoparticle formulation facilitated cellular accumulation of KP1019 (determined by ICP-MS measurements) resulting in significantly lowered IC50 values. With regard to the mode of action, increased cell cycle arrest in G2/M phase (PI-staining), DNA damage (Comet assay) as well as enhanced levels of apoptotic cell death (caspase 7 and PARP cleavage) were found in HCT116 cells treated with the new nanoformulation of KP1019. Summarizing, we present for the first time evidence that nanoformulation is a feasible strategy for improving the stability as well as activity of experimental anticancer Ruthenium Compounds.
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the Ruthenium Compound kp1339 potentiates the anticancer activity of sorafenib in vitro and in vivo
European Journal of Cancer, 2013Co-Authors: Petra Heffeter, Wilfried Korner, Bernhard K Keppler, Kushtrim Kryeziu, Ute Jungwirth, Bihter Atil, Diana Groza, Gunda Koellensperger, Thomas Mohr, Walter BergerAbstract:KP1339 is a promising Ruthenium-based anticancer Compound in early clinical development. This study aimed to test the effects of KP1339 on the in vitro and in vivo activity of the multi-kinase inhibitor sorafenib, the current standard first-line therapy for advanced hepatoma. Anticancer activity of the parental Compounds as compared to the drug combination was tested against a panel of cancer cell lines with a focus on hepatoma. Combination of KP1339 with sorafenib induced in the majority of all cases distinctly synergistic effects, comprising both sorafenib-resistant as well as sorafenib-responsive cell models. Several mechanisms were found to underlie these multifaceted synergistic activities. Firstly, co-exposure induced significantly enhanced accumulation levels of both drugs resulting in enhanced apoptosis induction. Secondly, sorafenib blocked KP1339-mediated activation of P38 signalling representing a protective response against the Ruthenium drug. In addition, sorafenib treatment also abrogated KP1339-induced G2/M arrest but resulted in check point-independent DNA-synthesis block and a complete loss of the mitotic cell populations. The activity of the KP1339/sorafenib combination was evaluated in the Hep3B hepatoma xenograft. KP1339 monotherapy led to a 2.4-fold increase in life span and, thus, was superior to sorafenib, which induced a 1.9-fold prolonged survival. The combined therapy further enhanced the mean survival by 3.9-fold. Synergistic activity was also observed in the VM-1 melanoma xenograft harbouring an activating braf mutation. Together, our data indicate that the combination of KP1339 with sorafenib displays promising activity in vitro and in vivo especially against human hepatoma models.
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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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organometallic anticancer complexes of lapachol metal centre dependent formation of reactive oxygen species and correlation with cytotoxicity
Chemical Communications, 2013Co-Authors: Wolfgang Kandioller, Michael A Jakupec, Bernhard K Keppler, Samuel M Meier, Walter Berger, Evelyn Balsano, Ute Jungwirth, Simone Goschl, Alexander Roller, Christian G HartingerAbstract:Organometallic Ru(II), Os(II) and Rh(III) complexes of lapachol induce apoptosis in human tumour cell lines in the low μM range by a mode of action involving oxidative stress, especially in the case of the Ruthenium Compound.
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inhibitory effects of the Ruthenium complex kp1019 in models of mammary cancer cell migration and invasion
Metal-based Drugs, 2009Co-Authors: Alberta Bergamo, Michael A Jakupec, Bernhard K Keppler, Alessia Masi, Gianni SavaAbstract:The effects of indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, or FFC14A), the second Ruthenium Compound that entered clinical trials, in an in vitro model of tumour invasion and metastasis show that the antitumour effects of this Compound might include also the modulation of cell behaviour although its cytotoxicity appears to be predominant over these effects. The comparison with its imidazole analogue KP418 shows however its superiority, being able to control in vitro cell growth and in some instances also in vivo tumour development. These results suggest that the activity of KP1019 is predominantly due to direct cytotoxic effects for tumour cells, evident also in vivo on primary tumour growth and that the effects on modulation of the biological behaviour of the cancer cell can be present but might have only a partial role.
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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 Micksche - 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.
Bernhard K Keppler - One of the best experts on this subject based on the ideXlab platform.
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nanoformulation improves activity of the pre clinical anticancer Ruthenium complex kp1019
Journal of Biomedical Nanotechnology, 2014Co-Authors: Petra Heffeter, Tetyana Konstantinova, Wilfried Korner, Bernhard K Keppler, Christian R Kowol, Anna Riabtseva, Y Senkiv, U Jungwith, Nataliya Mitina, I B YanchukAbstract:: Ruthenium anticancer drugs belong to the most promising non-platinum anticancer metal Compounds in clinical evaluation. However, although the clinical results are promising regarding both activity and very low adverse effects, the clinical application is currently hampered by the limited solubility and stability of the drug in aqueous solution. Here, we present a new nanoparticle formulation based on polymer-based micelles loaded with the anticancer lead Ruthenium Compound KP1019. Nanoprepared KP1019 was characterised by enhanced stability in aqueous solutions. Moreover, the nanoparticle formulation facilitated cellular accumulation of KP1019 (determined by ICP-MS measurements) resulting in significantly lowered IC50 values. With regard to the mode of action, increased cell cycle arrest in G2/M phase (PI-staining), DNA damage (Comet assay) as well as enhanced levels of apoptotic cell death (caspase 7 and PARP cleavage) were found in HCT116 cells treated with the new nanoformulation of KP1019. Summarizing, we present for the first time evidence that nanoformulation is a feasible strategy for improving the stability as well as activity of experimental anticancer Ruthenium Compounds.
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poly lactic acid nanoparticles of the lead anticancer Ruthenium Compound kp1019 and its surfactant mediated activation
Dalton Transactions, 2014Co-Authors: Britta Fischer, Petra Heffeter, Kushtrim Kryeziu, Samuel M Meier, Christian R Kowol, Walter Berger, Lars Gille, Bernhard K KepplerAbstract:Nanoparticle formulations offer besides the advantage of passive drug targeting also the opportunity to increase the stability of drugs. KP1019 is a lead Ruthenium(III) Compound which has been successfully tested in a clinical phase I trial. However, it is characterized by low stability in aqueous solution especially at physiological pH. To overcome this limitation, poly(lactic acid) (PLA) nanoparticles of KP1019 with two different surfactants (Pluronic F68 and Tween 80) were prepared by a single oil-in-water (o/w) emulsion. Cytotoxicity measurements comparing different aged Tween 80 nanoparticles revealed that the color change from brown to green was associated with an up to 20 fold increased activity compared to “free” KP1019. Further investigations suggested that this is based on the formation of enhanced intracellular reactive oxygen species levels. Additional studies revealed that the origin of the green color is a reaction between KP1019 and Tween 80. Kinetic studies of this reaction mixture using UV-Vis, ESI-MS and ESR spectroscopy indicated on the one hand a coordination of Tween 80 to KP1019, and on the other hand, the color change was found to correlate with a reduction of the Ru(III) center by the surfactant. Together, the results provide a first experimental approach to stabilize a biologically active Ru(II) species of KP1019 in aqueous solution, which probably can be also used to selectively generate this activated species in the tumor tissue via delivery of KP1019 using Tween 80 nanoparticles.
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the Ruthenium Compound kp1339 potentiates the anticancer activity of sorafenib in vitro and in vivo
European Journal of Cancer, 2013Co-Authors: Petra Heffeter, Wilfried Korner, Bernhard K Keppler, Kushtrim Kryeziu, Ute Jungwirth, Bihter Atil, Diana Groza, Gunda Koellensperger, Thomas Mohr, Walter BergerAbstract:KP1339 is a promising Ruthenium-based anticancer Compound in early clinical development. This study aimed to test the effects of KP1339 on the in vitro and in vivo activity of the multi-kinase inhibitor sorafenib, the current standard first-line therapy for advanced hepatoma. Anticancer activity of the parental Compounds as compared to the drug combination was tested against a panel of cancer cell lines with a focus on hepatoma. Combination of KP1339 with sorafenib induced in the majority of all cases distinctly synergistic effects, comprising both sorafenib-resistant as well as sorafenib-responsive cell models. Several mechanisms were found to underlie these multifaceted synergistic activities. Firstly, co-exposure induced significantly enhanced accumulation levels of both drugs resulting in enhanced apoptosis induction. Secondly, sorafenib blocked KP1339-mediated activation of P38 signalling representing a protective response against the Ruthenium drug. In addition, sorafenib treatment also abrogated KP1339-induced G2/M arrest but resulted in check point-independent DNA-synthesis block and a complete loss of the mitotic cell populations. The activity of the KP1339/sorafenib combination was evaluated in the Hep3B hepatoma xenograft. KP1339 monotherapy led to a 2.4-fold increase in life span and, thus, was superior to sorafenib, which induced a 1.9-fold prolonged survival. The combined therapy further enhanced the mean survival by 3.9-fold. Synergistic activity was also observed in the VM-1 melanoma xenograft harbouring an activating braf mutation. Together, our data indicate that the combination of KP1339 with sorafenib displays promising activity in vitro and in vivo especially against human hepatoma models.
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organometallic anticancer complexes of lapachol metal centre dependent formation of reactive oxygen species and correlation with cytotoxicity
Chemical Communications, 2013Co-Authors: Wolfgang Kandioller, Michael A Jakupec, Bernhard K Keppler, Samuel M Meier, Walter Berger, Evelyn Balsano, Ute Jungwirth, Simone Goschl, Alexander Roller, Christian G HartingerAbstract:Organometallic Ru(II), Os(II) and Rh(III) complexes of lapachol induce apoptosis in human tumour cell lines in the low μM range by a mode of action involving oxidative stress, especially in the case of the Ruthenium Compound.
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inhibitory effects of the Ruthenium complex kp1019 in models of mammary cancer cell migration and invasion
Metal-based Drugs, 2009Co-Authors: Alberta Bergamo, Michael A Jakupec, Bernhard K Keppler, Alessia Masi, Gianni SavaAbstract:The effects of indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, or FFC14A), the second Ruthenium Compound that entered clinical trials, in an in vitro model of tumour invasion and metastasis show that the antitumour effects of this Compound might include also the modulation of cell behaviour although its cytotoxicity appears to be predominant over these effects. The comparison with its imidazole analogue KP418 shows however its superiority, being able to control in vitro cell growth and in some instances also in vivo tumour development. These results suggest that the activity of KP1019 is predominantly due to direct cytotoxic effects for tumour cells, evident also in vivo on primary tumour growth and that the effects on modulation of the biological behaviour of the cancer cell can be present but might have only a partial role.
