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dc.creatorKopecka, J
dc.creatorPorto, S
dc.creatorLusa, S
dc.creatorGazzano, E
dc.creatorSalzano, G
dc.creatorGiordano, A
dc.creatorDesiderio, V
dc.creatorGhigo, D
dc.creatorCaraglia, M
dc.creatorDe Rosa, G
dc.creatorRiganti, C
dc.date.accessioned2021-01-29T22:22:14Z
dc.date.available2021-01-29T22:22:14Z
dc.date.issued2015-01-01
dc.identifier.issn1949-2553
dc.identifier.issn1949-2553
dc.identifier.doihttp://dx.doi.org/10.34944/dspace/5235
dc.identifier.other26372812 (pubmed)
dc.identifier.urihttp://hdl.handle.net/20.500.12613/5253
dc.description.abstractThe overexpression of ATP binding cassette (ABC) transporters makes tumor cells simultaneously resistant to several cytotoxic drugs. Impairing the energy metabolism of multidrug resistant (MDR) cells is a promising chemosensitizing strategy, but many metabolic modifiers are too toxic in vivo. We previously observed that the aminobisphosphonate zoledronic acid inhibits the activity of hypoxia inducible factor-1α (HIF-1α), a master regulator of cancer cell metabolism. Free zoledronic acid, however, reaches low intratumor concentration. We synthesized nanoparticle formulations of the aminobisphosphonate that allow a higher intratumor delivery of the drug. We investigated whether they are effective metabolic modifiers and chemosensitizing agents against human MDR cancer cells in vitro and in vivo. At not toxic dosage, nanoparticles carrying zoledronic acid chemosensitized MDR cells to a broad spectrum of cytotoxic drugs, independently of the type of ABC transporters expressed. The nanoparticles inhibited the isoprenoid synthesis and the Ras/ERK1/2-driven activation of HIF-1α, decreased the transcription and activity of glycolytic enzymes, the glucose flux through the glycolysis and tricarboxylic acid cycle, the electron flux through the mitochondrial respiratory chain, the synthesis of ATP. So doing, they lowered the ATP-dependent activity of ABC transporters, increasing the chemotherapy efficacy in vitro and in vivo. These effects were more pronounced in MDR cells than in chemosensitive ones and were due to the inhibition of farnesyl pyrophosphate synthase (FPPS), as demonstrated in FPPS-silenced tumors. Our work proposes nanoparticle formulations of zoledronic acid as the first not toxic metabolic modifiers, effective against MDR tumors.
dc.format.extent31461-31478
dc.language.isoen
dc.relation.haspartOncotarget
dc.relation.isreferencedbyImpact Journals, LLC
dc.rightsCC BY
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/
dc.subjectself-assembling nanoparticles
dc.subjectzoledronic acid
dc.subjectATP binding cassette transporters
dc.subjectmultidrug resistance
dc.subjecthypoxia inducible factor-1 alpha
dc.titleSelf-assembling nanoparticles encapsulating zoledronic acid revert multidrug resistance in cancer cells
dc.typeArticle
dc.type.genreJournal Article
dc.relation.doi10.18632/oncotarget.5058
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.creator.orcidGiordano, Antonio|0000-0002-5959-016X
dc.date.updated2021-01-29T22:22:10Z
refterms.dateFOA2021-01-29T22:22:15Z


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