Temozolomide down-regulates P-glycoprotein in human blood-brain barrier cells by disrupting Wnt3 signaling

Chiara Riganti, Iris C. Salaroglio, Martha L. Pinzòn-Daza, Valentina Caldera, Ivana Campia, Joanna Kopecka, Marta Mellai, Laura Annovazzi, Pierre Olivier Couraud, Amalia Bosia, Dario Ghigo, Davide Schiffer

    Resultado de la investigación: Contribución a RevistaArtículo

    24 Citas (Scopus)

    Resumen

    Low delivery of many anticancer drugs across the blood-brain barrier (BBB) is a limitation to the success of chemotherapy in glioblastoma. This is because of the high levels of ATP-binding cassette transporters like P-glycoprotein (Pgp/ABCB1), which effluxes drugs back to the bloodstream. Temozolomide is one of the few agents able to cross the BBB; its effects on BBB cells permeability and Pgp activity are not known. We found that temozolomide, at therapeutic concentration, increased the transport of Pgp substrates across human brain microvascular endothelial cells and decreased the expression of Pgp. By methylating the promoter of Wnt3 gene, temozolomide lowers the endogenous synthesis of Wnt3 in BBB cells, disrupts the Wnt3/glycogen synthase kinase 3/β-catenin signaling, and reduces the binding of β-catenin on the promoter of mdr1 gene, which encodes for Pgp. In co-culture models of BBB cells and human glioblastoma cells, pre-treatment with temozolomide increases the delivery, cytotoxicity, and antiproliferative effects of doxorubicin, vinblastine, and topotecan, three substrates of Pgp that are usually poorly delivered across BBB. Our work suggests that temozolomide increases the BBB permeability of drugs that are normally effluxed by Pgp back to the bloodstream. These findings may pave the way to new combinatorial chemotherapy schemes in glioblastoma. © 2013 Springer Basel.
    Idioma originalEnglish (US)
    Páginas (desde-hasta)499-516
    Número de páginas18
    PublicaciónCellular and Molecular Life Sciences
    DOI
    EstadoPublished - feb 1 2014

    Huella dactilar

    temozolomide
    P-Glycoprotein
    Blood-Brain Barrier
    Down-Regulation
    Glioblastoma
    beta Catenin
    Permeability
    Pharmaceutical Preparations
    Topotecan
    Drug Therapy
    ATP-Binding Cassette Transporters
    Vinblastine
    Coculture Techniques
    Doxorubicin
    Genes

    Citar esto

    Riganti, C., Salaroglio, I. C., Pinzòn-Daza, M. L., Caldera, V., Campia, I., Kopecka, J., ... Schiffer, D. (2014). Temozolomide down-regulates P-glycoprotein in human blood-brain barrier cells by disrupting Wnt3 signaling. Cellular and Molecular Life Sciences, 499-516. https://doi.org/10.1007/s00018-013-1397-y
    Riganti, Chiara ; Salaroglio, Iris C. ; Pinzòn-Daza, Martha L. ; Caldera, Valentina ; Campia, Ivana ; Kopecka, Joanna ; Mellai, Marta ; Annovazzi, Laura ; Couraud, Pierre Olivier ; Bosia, Amalia ; Ghigo, Dario ; Schiffer, Davide. / Temozolomide down-regulates P-glycoprotein in human blood-brain barrier cells by disrupting Wnt3 signaling. En: Cellular and Molecular Life Sciences. 2014 ; pp. 499-516.
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    title = "Temozolomide down-regulates P-glycoprotein in human blood-brain barrier cells by disrupting Wnt3 signaling",
    abstract = "Low delivery of many anticancer drugs across the blood-brain barrier (BBB) is a limitation to the success of chemotherapy in glioblastoma. This is because of the high levels of ATP-binding cassette transporters like P-glycoprotein (Pgp/ABCB1), which effluxes drugs back to the bloodstream. Temozolomide is one of the few agents able to cross the BBB; its effects on BBB cells permeability and Pgp activity are not known. We found that temozolomide, at therapeutic concentration, increased the transport of Pgp substrates across human brain microvascular endothelial cells and decreased the expression of Pgp. By methylating the promoter of Wnt3 gene, temozolomide lowers the endogenous synthesis of Wnt3 in BBB cells, disrupts the Wnt3/glycogen synthase kinase 3/β-catenin signaling, and reduces the binding of β-catenin on the promoter of mdr1 gene, which encodes for Pgp. In co-culture models of BBB cells and human glioblastoma cells, pre-treatment with temozolomide increases the delivery, cytotoxicity, and antiproliferative effects of doxorubicin, vinblastine, and topotecan, three substrates of Pgp that are usually poorly delivered across BBB. Our work suggests that temozolomide increases the BBB permeability of drugs that are normally effluxed by Pgp back to the bloodstream. These findings may pave the way to new combinatorial chemotherapy schemes in glioblastoma. {\circledC} 2013 Springer Basel.",
    author = "Chiara Riganti and Salaroglio, {Iris C.} and Pinz{\`o}n-Daza, {Martha L.} and Valentina Caldera and Ivana Campia and Joanna Kopecka and Marta Mellai and Laura Annovazzi and Couraud, {Pierre Olivier} and Amalia Bosia and Dario Ghigo and Davide Schiffer",
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    doi = "10.1007/s00018-013-1397-y",
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    Riganti, C, Salaroglio, IC, Pinzòn-Daza, ML, Caldera, V, Campia, I, Kopecka, J, Mellai, M, Annovazzi, L, Couraud, PO, Bosia, A, Ghigo, D & Schiffer, D 2014, 'Temozolomide down-regulates P-glycoprotein in human blood-brain barrier cells by disrupting Wnt3 signaling', Cellular and Molecular Life Sciences, pp. 499-516. https://doi.org/10.1007/s00018-013-1397-y

    Temozolomide down-regulates P-glycoprotein in human blood-brain barrier cells by disrupting Wnt3 signaling. / Riganti, Chiara; Salaroglio, Iris C.; Pinzòn-Daza, Martha L.; Caldera, Valentina; Campia, Ivana; Kopecka, Joanna; Mellai, Marta; Annovazzi, Laura; Couraud, Pierre Olivier; Bosia, Amalia; Ghigo, Dario; Schiffer, Davide.

    En: Cellular and Molecular Life Sciences, 01.02.2014, p. 499-516.

    Resultado de la investigación: Contribución a RevistaArtículo

    TY - JOUR

    T1 - Temozolomide down-regulates P-glycoprotein in human blood-brain barrier cells by disrupting Wnt3 signaling

    AU - Riganti, Chiara

    AU - Salaroglio, Iris C.

    AU - Pinzòn-Daza, Martha L.

    AU - Caldera, Valentina

    AU - Campia, Ivana

    AU - Kopecka, Joanna

    AU - Mellai, Marta

    AU - Annovazzi, Laura

    AU - Couraud, Pierre Olivier

    AU - Bosia, Amalia

    AU - Ghigo, Dario

    AU - Schiffer, Davide

    PY - 2014/2/1

    Y1 - 2014/2/1

    N2 - Low delivery of many anticancer drugs across the blood-brain barrier (BBB) is a limitation to the success of chemotherapy in glioblastoma. This is because of the high levels of ATP-binding cassette transporters like P-glycoprotein (Pgp/ABCB1), which effluxes drugs back to the bloodstream. Temozolomide is one of the few agents able to cross the BBB; its effects on BBB cells permeability and Pgp activity are not known. We found that temozolomide, at therapeutic concentration, increased the transport of Pgp substrates across human brain microvascular endothelial cells and decreased the expression of Pgp. By methylating the promoter of Wnt3 gene, temozolomide lowers the endogenous synthesis of Wnt3 in BBB cells, disrupts the Wnt3/glycogen synthase kinase 3/β-catenin signaling, and reduces the binding of β-catenin on the promoter of mdr1 gene, which encodes for Pgp. In co-culture models of BBB cells and human glioblastoma cells, pre-treatment with temozolomide increases the delivery, cytotoxicity, and antiproliferative effects of doxorubicin, vinblastine, and topotecan, three substrates of Pgp that are usually poorly delivered across BBB. Our work suggests that temozolomide increases the BBB permeability of drugs that are normally effluxed by Pgp back to the bloodstream. These findings may pave the way to new combinatorial chemotherapy schemes in glioblastoma. © 2013 Springer Basel.

    AB - Low delivery of many anticancer drugs across the blood-brain barrier (BBB) is a limitation to the success of chemotherapy in glioblastoma. This is because of the high levels of ATP-binding cassette transporters like P-glycoprotein (Pgp/ABCB1), which effluxes drugs back to the bloodstream. Temozolomide is one of the few agents able to cross the BBB; its effects on BBB cells permeability and Pgp activity are not known. We found that temozolomide, at therapeutic concentration, increased the transport of Pgp substrates across human brain microvascular endothelial cells and decreased the expression of Pgp. By methylating the promoter of Wnt3 gene, temozolomide lowers the endogenous synthesis of Wnt3 in BBB cells, disrupts the Wnt3/glycogen synthase kinase 3/β-catenin signaling, and reduces the binding of β-catenin on the promoter of mdr1 gene, which encodes for Pgp. In co-culture models of BBB cells and human glioblastoma cells, pre-treatment with temozolomide increases the delivery, cytotoxicity, and antiproliferative effects of doxorubicin, vinblastine, and topotecan, three substrates of Pgp that are usually poorly delivered across BBB. Our work suggests that temozolomide increases the BBB permeability of drugs that are normally effluxed by Pgp back to the bloodstream. These findings may pave the way to new combinatorial chemotherapy schemes in glioblastoma. © 2013 Springer Basel.

    U2 - 10.1007/s00018-013-1397-y

    DO - 10.1007/s00018-013-1397-y

    M3 - Article

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    EP - 516

    JO - Cellular and Molecular Life Sciences

    JF - Cellular and Molecular Life Sciences

    SN - 1420-682X

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