Zoledronic acid-encapsulating self-assembling nanoparticles and doxorubicin: A combinatorial approach to overcome simultaneously chemoresistance and immunoresistance in breast tumors

Joanna Kopecka, Stefania Porto, Sara Lusa, Elena Gazzano, Giuseppina Salzano, Martha Leonor Pinzòn-Daza, Antonio Giordano, Vincenzo Desiderio, Dario Ghigo, Giuseppe De Rosa, Michele Caraglia, Chiara Riganti

    Resultado de la investigación: Contribución a RevistaArtículo

    11 Citas (Scopus)

    Resumen

    The resistance to chemotherapy and the tumor escape from host immunosurveillance are the main causes of the failure of anthracycline-based regimens in breast cancer, where an effective chemo-immunosensitizing strategy is lacking. The clinically used aminobisphosphonate zoledronic acid (ZA) reverses chemoresistance and immunoresistance in vitro. Previously we developed a nanoparticle-based zoledronic acid-containing formulation (NZ) that allowed a higher intratumor delivery of the drug compared with free ZA in vivo. We tested its efficacy in combination with doxorubicin in breast tumors refractory to chemotherapy and immune system recognition as a new combinatorial approach to produce chemo- and immunosensitization. NZ reduced the IC50 of doxorubicin in human and murine chemoresistant breast cancer cells and restored the doxorubicin efficacy against chemo-immunoresistant tumors implanted in immunocompetent mice. By reducing the metabolic flux through the mevalonate pathway, NZ lowered the activity of Ras/ERK1/2/HIF-1α axis and the expression of P-glycoprotein, decreased the glycolysis and the mitochondrial respiratory chain, induced a cytochrome c/caspase 9/caspase 3-dependent apoptosis, thus restoring the direct cytotoxic effects of doxorubicin on tumor cell. Moreover, NZ restored the doxorubicin-induced immunogenic cell death and reversed the tumorinduced immunosuppression due to the production of kynurenine, by inhibiting the STAT3/indoleamine 2,3 dioxygenase axis. These events increased the number of dendritic cells and decreased the number of immunosuppressive T-regulatory cells infiltrating the tumors. Our work proposes the use of nanoparticle encapsulating zoledronic acid as an effective tool overcoming at the same time chemoresistance and immunoresistance in breast tumors, thanks to the effects exerted on tumor cell and tumor-infiltrating immune cells.
    Idioma originalEnglish (US)
    Páginas (desde-hasta)20753-20772
    Número de páginas20
    PublicaciónOncotarget
    DOI
    EstadoPublished - abr 12 2016

    Huella dactilar

    zoledronic acid
    Nanoparticles
    Doxorubicin
    Breast Neoplasms
    Neoplasms
    Indoleamine-Pyrrole 2,3,-Dioxygenase
    Tumor Escape
    Kynurenine
    Immunologic Monitoring
    Drug Therapy
    Mevalonic Acid
    Caspase 9
    Anthracyclines
    P-Glycoprotein
    Glycolysis
    Regulatory T-Lymphocytes
    Immunosuppressive Agents
    Electron Transport
    Cytochromes c
    Caspase 3

    Citar esto

    Kopecka, Joanna ; Porto, Stefania ; Lusa, Sara ; Gazzano, Elena ; Salzano, Giuseppina ; Pinzòn-Daza, Martha Leonor ; Giordano, Antonio ; Desiderio, Vincenzo ; Ghigo, Dario ; De Rosa, Giuseppe ; Caraglia, Michele ; Riganti, Chiara. / Zoledronic acid-encapsulating self-assembling nanoparticles and doxorubicin: A combinatorial approach to overcome simultaneously chemoresistance and immunoresistance in breast tumors. En: Oncotarget. 2016 ; pp. 20753-20772.
    @article{78c18b994f544b52a33dc4eec3a7becf,
    title = "Zoledronic acid-encapsulating self-assembling nanoparticles and doxorubicin: A combinatorial approach to overcome simultaneously chemoresistance and immunoresistance in breast tumors",
    abstract = "The resistance to chemotherapy and the tumor escape from host immunosurveillance are the main causes of the failure of anthracycline-based regimens in breast cancer, where an effective chemo-immunosensitizing strategy is lacking. The clinically used aminobisphosphonate zoledronic acid (ZA) reverses chemoresistance and immunoresistance in vitro. Previously we developed a nanoparticle-based zoledronic acid-containing formulation (NZ) that allowed a higher intratumor delivery of the drug compared with free ZA in vivo. We tested its efficacy in combination with doxorubicin in breast tumors refractory to chemotherapy and immune system recognition as a new combinatorial approach to produce chemo- and immunosensitization. NZ reduced the IC50 of doxorubicin in human and murine chemoresistant breast cancer cells and restored the doxorubicin efficacy against chemo-immunoresistant tumors implanted in immunocompetent mice. By reducing the metabolic flux through the mevalonate pathway, NZ lowered the activity of Ras/ERK1/2/HIF-1α axis and the expression of P-glycoprotein, decreased the glycolysis and the mitochondrial respiratory chain, induced a cytochrome c/caspase 9/caspase 3-dependent apoptosis, thus restoring the direct cytotoxic effects of doxorubicin on tumor cell. Moreover, NZ restored the doxorubicin-induced immunogenic cell death and reversed the tumorinduced immunosuppression due to the production of kynurenine, by inhibiting the STAT3/indoleamine 2,3 dioxygenase axis. These events increased the number of dendritic cells and decreased the number of immunosuppressive T-regulatory cells infiltrating the tumors. Our work proposes the use of nanoparticle encapsulating zoledronic acid as an effective tool overcoming at the same time chemoresistance and immunoresistance in breast tumors, thanks to the effects exerted on tumor cell and tumor-infiltrating immune cells.",
    author = "Joanna Kopecka and Stefania Porto and Sara Lusa and Elena Gazzano and Giuseppina Salzano and Pinz{\`o}n-Daza, {Martha Leonor} and Antonio Giordano and Vincenzo Desiderio and Dario Ghigo and {De Rosa}, Giuseppe and Michele Caraglia and Chiara Riganti",
    year = "2016",
    month = "4",
    day = "12",
    doi = "10.18632/oncotarget.8012",
    language = "English (US)",
    pages = "20753--20772",
    journal = "Oncotarget",
    issn = "1949-2553",
    publisher = "Impact Journals",

    }

    Kopecka, J, Porto, S, Lusa, S, Gazzano, E, Salzano, G, Pinzòn-Daza, ML, Giordano, A, Desiderio, V, Ghigo, D, De Rosa, G, Caraglia, M & Riganti, C 2016, 'Zoledronic acid-encapsulating self-assembling nanoparticles and doxorubicin: A combinatorial approach to overcome simultaneously chemoresistance and immunoresistance in breast tumors', Oncotarget, pp. 20753-20772. https://doi.org/10.18632/oncotarget.8012

    Zoledronic acid-encapsulating self-assembling nanoparticles and doxorubicin: A combinatorial approach to overcome simultaneously chemoresistance and immunoresistance in breast tumors. / Kopecka, Joanna; Porto, Stefania; Lusa, Sara; Gazzano, Elena; Salzano, Giuseppina; Pinzòn-Daza, Martha Leonor; Giordano, Antonio; Desiderio, Vincenzo; Ghigo, Dario; De Rosa, Giuseppe; Caraglia, Michele; Riganti, Chiara.

    En: Oncotarget, 12.04.2016, p. 20753-20772.

    Resultado de la investigación: Contribución a RevistaArtículo

    TY - JOUR

    T1 - Zoledronic acid-encapsulating self-assembling nanoparticles and doxorubicin: A combinatorial approach to overcome simultaneously chemoresistance and immunoresistance in breast tumors

    AU - Kopecka, Joanna

    AU - Porto, Stefania

    AU - Lusa, Sara

    AU - Gazzano, Elena

    AU - Salzano, Giuseppina

    AU - Pinzòn-Daza, Martha Leonor

    AU - Giordano, Antonio

    AU - Desiderio, Vincenzo

    AU - Ghigo, Dario

    AU - De Rosa, Giuseppe

    AU - Caraglia, Michele

    AU - Riganti, Chiara

    PY - 2016/4/12

    Y1 - 2016/4/12

    N2 - The resistance to chemotherapy and the tumor escape from host immunosurveillance are the main causes of the failure of anthracycline-based regimens in breast cancer, where an effective chemo-immunosensitizing strategy is lacking. The clinically used aminobisphosphonate zoledronic acid (ZA) reverses chemoresistance and immunoresistance in vitro. Previously we developed a nanoparticle-based zoledronic acid-containing formulation (NZ) that allowed a higher intratumor delivery of the drug compared with free ZA in vivo. We tested its efficacy in combination with doxorubicin in breast tumors refractory to chemotherapy and immune system recognition as a new combinatorial approach to produce chemo- and immunosensitization. NZ reduced the IC50 of doxorubicin in human and murine chemoresistant breast cancer cells and restored the doxorubicin efficacy against chemo-immunoresistant tumors implanted in immunocompetent mice. By reducing the metabolic flux through the mevalonate pathway, NZ lowered the activity of Ras/ERK1/2/HIF-1α axis and the expression of P-glycoprotein, decreased the glycolysis and the mitochondrial respiratory chain, induced a cytochrome c/caspase 9/caspase 3-dependent apoptosis, thus restoring the direct cytotoxic effects of doxorubicin on tumor cell. Moreover, NZ restored the doxorubicin-induced immunogenic cell death and reversed the tumorinduced immunosuppression due to the production of kynurenine, by inhibiting the STAT3/indoleamine 2,3 dioxygenase axis. These events increased the number of dendritic cells and decreased the number of immunosuppressive T-regulatory cells infiltrating the tumors. Our work proposes the use of nanoparticle encapsulating zoledronic acid as an effective tool overcoming at the same time chemoresistance and immunoresistance in breast tumors, thanks to the effects exerted on tumor cell and tumor-infiltrating immune cells.

    AB - The resistance to chemotherapy and the tumor escape from host immunosurveillance are the main causes of the failure of anthracycline-based regimens in breast cancer, where an effective chemo-immunosensitizing strategy is lacking. The clinically used aminobisphosphonate zoledronic acid (ZA) reverses chemoresistance and immunoresistance in vitro. Previously we developed a nanoparticle-based zoledronic acid-containing formulation (NZ) that allowed a higher intratumor delivery of the drug compared with free ZA in vivo. We tested its efficacy in combination with doxorubicin in breast tumors refractory to chemotherapy and immune system recognition as a new combinatorial approach to produce chemo- and immunosensitization. NZ reduced the IC50 of doxorubicin in human and murine chemoresistant breast cancer cells and restored the doxorubicin efficacy against chemo-immunoresistant tumors implanted in immunocompetent mice. By reducing the metabolic flux through the mevalonate pathway, NZ lowered the activity of Ras/ERK1/2/HIF-1α axis and the expression of P-glycoprotein, decreased the glycolysis and the mitochondrial respiratory chain, induced a cytochrome c/caspase 9/caspase 3-dependent apoptosis, thus restoring the direct cytotoxic effects of doxorubicin on tumor cell. Moreover, NZ restored the doxorubicin-induced immunogenic cell death and reversed the tumorinduced immunosuppression due to the production of kynurenine, by inhibiting the STAT3/indoleamine 2,3 dioxygenase axis. These events increased the number of dendritic cells and decreased the number of immunosuppressive T-regulatory cells infiltrating the tumors. Our work proposes the use of nanoparticle encapsulating zoledronic acid as an effective tool overcoming at the same time chemoresistance and immunoresistance in breast tumors, thanks to the effects exerted on tumor cell and tumor-infiltrating immune cells.

    U2 - 10.18632/oncotarget.8012

    DO - 10.18632/oncotarget.8012

    M3 - Article

    SP - 20753

    EP - 20772

    JO - Oncotarget

    JF - Oncotarget

    SN - 1949-2553

    ER -