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Kees Nooter - One of the best experts on this subject based on the ideXlab platform.

  • chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the abcg2 bcrp and abcb1 mdr1 drug transport pumps
    Cancer Biology & Therapy, 2005
    Co-Authors: Herman Burger, Hans Van Tol, Mariel Brok, Erik A C Wiemer, Ernst A De Bruijn, Gunther Guetens, Gert De Boeck, Alex Sparreboom, Jaap Verweij, Kees Nooter
    Abstract:

    Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumours. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco-2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure (up to 100 days) with imatinib (10 ?M) specifically upregulates the expression of ABCG2 (maximal ~17-fold) and ABCB1 (maximal ~5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco-2 cells resulted in a ~50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- an...

  • chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the abcg2 bcrp and abcb1 mdr1 drug transport pumps
    Cancer Biology & Therapy, 2005
    Co-Authors: Herman Burger, Hans Van Tol, Mariel Brok, Erik A C Wiemer, Ernst A De Bruijn, Gunther Guetens, Gert De Boeck, Alex Sparreboom, Jaap Verweij, Kees Nooter
    Abstract:

    Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumors. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure (up to 100 days) with imatinib (10 microM) specifically upregulates the expression of ABCG2 (maximal approximately 17-fold) and ABCB1 (maximal approximately 5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco2 cells resulted in a approximately 50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- and ABCB1-mediated efflux, as a result of upregulated expression of these drug pumps. Both ABCG2 and ABCB1 are normally expressed in the gastrointestinal tract and it might be anticipated that drug-induced upregulation of these intestinal pumps could reduce the oral bioavailability of imatinib, representing a novel mechanism of acquired pharmacokinetic drug resistance in cancer patients that are chronically treated with imatinib.

Justine Marchand - One of the best experts on this subject based on the ideXlab platform.

  • effects of hg sublethal exposure in the brain of peacock blennies salaria pavo molecular physiological and histopathological analysis
    Chemosphere, 2018
    Co-Authors: Azza Naija, Benoit Chenais, Zohra Haouas, Ahmed Noureddine Helal, Patrick Kestemont, Ronny Blust, Justine Marchand
    Abstract:

    Abstract Marine environments are affected by large amounts of toxicants among those mercury (Hg). The aim of this study was to assess potential neurotoxic effects of Hg in the peacock blenny Salaria pavo . A sublethal contamination to 66 μg HgCl 2 L −1 over periods of 1, 4, 10 and 15 days was performed. Total Hg concentrations measured in the brain highlighted the detection of Hg at days 1 and 4 following the exposure but no concentration of the metal was further detected. Partial-length cDNA of genes coding ABC transporters ( abcb1 , ABCC1 , abcc2 , abcg2 ) and acetylcholinesterase ( ache ) were characterized. Results from mRNA expression levels displayed an up-regulation of abcb1 mRNA while a down-regulation of ABCC1 and abcc2 mRNA was observed. No change in abcg2 and ache mRNA expression was noted throughout the experiment. At each sampling time, Hg exposure did not affect the activity of the AChE enzyme. The histological analysis indicated that fish exhibited several damages in the optic tectum and the cerebellum and 3 reaction patterns were identified for each organ: circulatory disturbances, regressive and progressive changes. Molecular, physiological and histological biomarkers assessed in the present study highlighted that peacock blennies were able to detoxify Hg from the brain tissue by developing defense mechanisms. More globally, neurotoxic effects of a sublethal Hg exposure in the brain of peacock blennies and the adaptation capacity of this species were evaluated.

  • cadmium exposure exerts neurotoxic effects in peacock blennies salaria pavo
    Ecotoxicology and Environmental Safety, 2017
    Co-Authors: Azza Naija, Benoit Chenais, Zohra Haouas, Ahmed Noureddine Helal, Patrick Kestemont, Ronny Blust, Justine Marchand
    Abstract:

    Abstract Cadmium (Cd) is considered as an important factor involved in several neurological disturbances. The aim of this study was to assess the effects of Cd in the brain of peacock blennies Salaria pavo , a species used as a bioindicator of water pollution. A sublethal contamination of 2 mg CdCl 2 L −1 was performed over periods of 1, 4, 10 and 15 days. Total Cd accumulation was measured in brains and displayed low concentrations throughout the experiment. Partial-length cDNA of different ATP-binding cassette transporters ( abcb1 , ABCC1 , abcc2 , abcg2 proteins) and acetylcholinesterase ( ache ) were characterized. mRNA expressions profiles displayed an up-regulation of abcc2 mRNA after 4 days of Cd exposure only while abcg2 mRNA was down-regulated after 10 days only. For AChE, the mRNA transcription and the activity of the enzyme were followed and highlighted that Cd exerted an inhibitory effect on the nervous information transmission. At the histological level, fish exhibited pathological symptoms in the optic tectum and the cerebellum and results showed that the cerebellum was the most affected organ.

Alex Sparreboom - One of the best experts on this subject based on the ideXlab platform.

  • chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the abcg2 bcrp and abcb1 mdr1 drug transport pumps
    Cancer Biology & Therapy, 2005
    Co-Authors: Herman Burger, Hans Van Tol, Mariel Brok, Erik A C Wiemer, Ernst A De Bruijn, Gunther Guetens, Gert De Boeck, Alex Sparreboom, Jaap Verweij, Kees Nooter
    Abstract:

    Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumours. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco-2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure (up to 100 days) with imatinib (10 ?M) specifically upregulates the expression of ABCG2 (maximal ~17-fold) and ABCB1 (maximal ~5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco-2 cells resulted in a ~50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- an...

  • chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the abcg2 bcrp and abcb1 mdr1 drug transport pumps
    Cancer Biology & Therapy, 2005
    Co-Authors: Herman Burger, Hans Van Tol, Mariel Brok, Erik A C Wiemer, Ernst A De Bruijn, Gunther Guetens, Gert De Boeck, Alex Sparreboom, Jaap Verweij, Kees Nooter
    Abstract:

    Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumors. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure (up to 100 days) with imatinib (10 microM) specifically upregulates the expression of ABCG2 (maximal approximately 17-fold) and ABCB1 (maximal approximately 5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco2 cells resulted in a approximately 50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- and ABCB1-mediated efflux, as a result of upregulated expression of these drug pumps. Both ABCG2 and ABCB1 are normally expressed in the gastrointestinal tract and it might be anticipated that drug-induced upregulation of these intestinal pumps could reduce the oral bioavailability of imatinib, representing a novel mechanism of acquired pharmacokinetic drug resistance in cancer patients that are chronically treated with imatinib.

  • pharmacogenomics of abc transporters and its role in cancer chemotherapy
    Drug Resistance Updates, 2003
    Co-Authors: Alex Sparreboom, Romano Danesi, Yuichi Ando, Juliana Chan, William D Figg
    Abstract:

    ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2, cMOAT), and ABCG2 (BCRP, MXR, ABCP) are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenomics of ABC transporters, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer.

Herman Burger - One of the best experts on this subject based on the ideXlab platform.

  • chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the abcg2 bcrp and abcb1 mdr1 drug transport pumps
    Cancer Biology & Therapy, 2005
    Co-Authors: Herman Burger, Hans Van Tol, Mariel Brok, Erik A C Wiemer, Ernst A De Bruijn, Gunther Guetens, Gert De Boeck, Alex Sparreboom, Jaap Verweij, Kees Nooter
    Abstract:

    Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumours. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco-2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure (up to 100 days) with imatinib (10 ?M) specifically upregulates the expression of ABCG2 (maximal ~17-fold) and ABCB1 (maximal ~5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco-2 cells resulted in a ~50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- an...

  • chronic imatinib mesylate exposure leads to reduced intracellular drug accumulation by induction of the abcg2 bcrp and abcb1 mdr1 drug transport pumps
    Cancer Biology & Therapy, 2005
    Co-Authors: Herman Burger, Hans Van Tol, Mariel Brok, Erik A C Wiemer, Ernst A De Bruijn, Gunther Guetens, Gert De Boeck, Alex Sparreboom, Jaap Verweij, Kees Nooter
    Abstract:

    Imatinib mesylate is a selective tyrosine kinase inhibitor that is successfully used in the treatment of Philadelphia-positive chronic and acute leukaemia's, and gastrointestinal stromal tumors. We investigated whether the intended chronic oral administration of imatinib might lead to the induction of the intestinal ABC transport proteins ABCB1, ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2. Using Caco2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure (up to 100 days) with imatinib (10 microM) specifically upregulates the expression of ABCG2 (maximal approximately 17-fold) and ABCB1 (maximal approximately 5-fold). The induction of gene expression appeared to be biphasic in time, with a significant increase in ABCG2 and ABCB1 at day 3 and day 25, respectively, and was not mediated through activation of the human orphan nuclear receptor SXR/NR1I2. Importantly, chronic imatinib exposure of Caco2 cells resulted in a approximately 50% decrease in intracellular accumulation of imatinib, probably by enhanced ABCG2- and ABCB1-mediated efflux, as a result of upregulated expression of these drug pumps. Both ABCG2 and ABCB1 are normally expressed in the gastrointestinal tract and it might be anticipated that drug-induced upregulation of these intestinal pumps could reduce the oral bioavailability of imatinib, representing a novel mechanism of acquired pharmacokinetic drug resistance in cancer patients that are chronically treated with imatinib.

Thomas Langmann - One of the best experts on this subject based on the ideXlab platform.

  • Characterization of the ATP-binding cassette transporter gene expression profile in Y79: a retinoblastoma cell line
    Molecular and Cellular Biochemistry, 2009
    Co-Authors: Doris Hendig, Ralf Zarbock, Thomas Langmann, Knut Kleesiek, Gerd Schmitz, Christian Gotting
    Abstract:

    Chemotherapy failure was reported in treatment of retinoblastoma suggesting a role for ATP-binding cassette (ABC) proteins. Little is known about the expression pattern of ABC proteins in this cancer type. We investigated the gene expression profile of 47 ABC proteins in the human retinoblastoma cell line Y79 by TaqMan low-density array. Analysis revealed 31 ABC transporter genes expressed in this tumor cell line. Y79 cells demonstrate high gene expression of ABCA7 , ABCA12 , ABCB7 , ABCB10 , ABCC1 , ABCC4 , ABCD3 , ABCE1 , ABCF1 , ABCF2 , and ABCF3 (more than twofold compared to pooled RNA from different tissues). Moreover, we show that Y79 cells exhibit an active calcein efflux pointing to multidrug resistance protein (MRP)-like transporter activity. In summary, we present for the first time an ABC transporter gene expression profile in cells derived from retinoblastoma. Most of the highly expressed ABC transporter genes are typical markers of cancer cells and might exhibit potential targets for medical treatment of retinoblastoma.

  • mapping atp binding cassette transporter gene expression profiles in melanocytes and melanoma cells
    Melanoma Research, 2007
    Co-Authors: Susanne Heimerl, Thomas Langmann, Anja K Bosserhoff, Josef Ecker, Gerd Schmitz
    Abstract:

    ATP-binding cassette (ABC) transporters regulate the transport of a variety of physiologic substrates. Moreover, several human ABC proteins are responsible for drug exclusion in compound-treated tumor cells, providing cellular mechanisms for the development of multidrug resistance and, therefore, playing an important role in malignant transformation. As only limited information exists on the role of ABC transporters in melanoma, the aim of the study was to generate a complete expression profile of ABC transporters in this tumor entity. Using a TaqMan low-density array for 47 human ABC transporters, mRNA expression analysis was performed from normal human epidermal melanocytes (NHEM P2 and NHEM P3), nine different cell lines originating from primary melanoma (Mel Ei, Mel Juso, Mel Ho and Mel Wei), and metastases of malignant melanoma (Mel Im, Mel Ju, SK Mel 28, HTZ 19 and HMB2). Cell line-specific expression levels were compared with gene expression in pooled RNA from a variety of other human tissues. High expression levels were detected in pooled tissue RNA as well as in cells of melanocytic origin for ABCA5, ABCB2, ABCB6, ABCD3, ABCD4, ABCF1, ABCF2 and ABCF3, whereas ABCB5 revealed a melanocyte-specific high transcript level. In relation to normal melanocytes, ABCB3, ABCB6, ABCC2, ABCC4, ABCE1 and ABCF2 were significantly increased in melanoma cell lines, whereas ABCA7, ABCA12, ABCB2, ABCB4, ABCB5 and ABCD1 showed lower expression levels. In summary, we present here for the first time an ABC-transporter mRNA expression profile in melanoma in comparison to normal melanocytes. The differentially regulated ABC transporters detected by our approach may be candidate genes involved in melanoma tumorigenesis, progression and therapy resistance and could therefore be of great importance to identify novel options for melanoma therapy.

  • adenosine triphosphate binding cassette abc transporters are expressed and regulated during terminal keratinocyte differentiation a potential role for abca7 in epidermal lipid reorganization
    Journal of Investigative Dermatology, 2003
    Co-Authors: Danuta Kielar, Thomas Langmann, Wolfgang E Kaminski, Gerhard Liebisch, Armin Piehler, Jurgen J Wenzel, Christoph Mohle, Susanne Heimerl, Sven O Friedrich, Alfred Bottcher
    Abstract:

    Central aspects of the cellular lipid trafficking mechanisms that occur during keratinocyte differentiation are still not well understood. In the past years, evidence has accumulated to suggest that members of the superfamily of adenosine triphosphate binding cassette (ABC) transporters are critically involved in the transmembrane transport of cellular lipids. To test the hypothesis that ABC molecules are potentially involved in the epidermal transport of sphingolipids, glycerophospholipids, cholesterol, and fatty acids, we performed mRNA expression profiling of all currently known ABC molecules during in vitro differentiation of human keratinocytes and HaCaT cells. We identified six ABC molecules that displayed significant regulation during differentiation of these cells. The recently cloned transporter ABCA7 was highly expressed in keratinocytes and HaCaT cells and upregulated during differentiation. Overexpression of ABCA7 in HeLa cells resulted in increased expression of intracellular and cell surface ceramide and elevated intracellular phosphatidylserine levels. Given the observation that during terminal keratinocyte differentiation intracellular and surface ceramide levels are increased, our results render ABCA7 a candidate regulator of ceramide transport in this process. In addition to ABCA7, the cholesterol transporters ABCB1 and ABCG1 and the glutathione/glucuronide sulfate transporters ABCC1, ABCC3, and ABCC4, were strongly upregulated during keratinocyte and HaCaT cell differentiation. These findings support the notion that ABCB1 and ABCG1 are potentially implicated in cholesterol transport, whereas ABCC1, ABCC3, and ABCC4 are candidate regulators of the translocation of sulfated lipids during stratum corneum keratinization. Our results suggest specific biologic functions for members of the ABC transporter family in epidermal lipid reorganization during terminal keratinocyte differentiation.