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

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dc.contributor.gruplacBio-Biospa
dc.creatorKopecka, Joanna
dc.creatorPorto, Stefania
dc.creatorLusa, Sara
dc.creatorGazzano, Elena
dc.creatorSalzano, Giuseppina
dc.creatorPinzòn-Daza, Martha Leonor
dc.creatorGiordano, Antonio
dc.creatorDesiderio, Vincenzo
dc.creatorGhigo, Dario
dc.creatorDe Rosa, Giuseppe
dc.creatorCaraglia, Michele
dc.creatorRiganti, Chiara
dc.creator.googleKopecka, Joanna
dc.creator.googleLusa, Sara
dc.creator.googlePorto, Stefania
dc.creator.googleGazzano, Elena
dc.creator.googleSalzano, Giuseppina
dc.creator.googlePinzòn-Daza, Martha Leonor
dc.creator.googleGiordano, Antonio
dc.creator.googleDesiderio, Vincenzo
dc.creator.googleGhigo, Dario
dc.creator.googleDe Rosa, Giuseppe
dc.creator.googleCaraglia, Michele
dc.creator.googleRiganti, Chiara
dc.date.accessioned2018-04-10T13:56:17Z
dc.date.available2018-04-10T13:56:17Z
dc.date.created2016
dc.date.issued2016
dc.description.abstractThe 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-1? 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.eng
dc.format.mimetypeapplication/pdf
dc.identifier.issnISSN: 1949-2553
dc.identifier.urihttp://repository.urosario.edu.co/handle/10336/17810
dc.language.isoeng
dc.relation.citationEndPage20772
dc.relation.citationIssueNo. 12
dc.relation.citationStartPage20753
dc.relation.citationTitleOncotarget
dc.relation.citationVolumeVol. 15
dc.relation.ispartofOncotarget, ISSN: 1949-2553, Vol. 15/No.12 (April 2016) pp. 20753-20772spa
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991490/
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
dc.rights.accesoAbierto (Texto Completo)spa
dc.source.instnameinstname:Universidad del Rosario
dc.source.reponamereponame:Repositorio Institucional EdocUR
dc.subjectHipoxia De La Célulaspa
dc.subjectNeoplasias Del Cuello Uterinospa
dc.subjectCélulas Endotelialesspa
dc.subjectMicroambiente Tumoralspa
dc.subjectCélulas Helaspa
dc.subjectFactores De Transcripción Statspa
dc.subjectEstrés Fisiológicospa
dc.subject.ddcEnfermedades
dc.subject.decsNeoplasias de la Mamaspa
dc.subject.decsEpirrubicinaspa
dc.subject.decsPontos Quânticosspa
dc.subject.decsCélulas Tumorales Cultivadasspa
dc.subject.keywordSelf-Assembling Nanoparticleseng
dc.subject.keywordZoledronic Acideng
dc.subject.keywordDoxorubicin Resistanceeng
dc.subject.keywordImmunoresistanceeng
dc.subject.keywordImmunosuppressioneng
dc.titleZoledronic acid-encapsulating self-assembling nanoparticles and doxorubicin: a combinatorial approach to overcome simultaneously chemoresistance and immunoresistance in breast tumorsspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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