title: Mitochondria-Targeted Doxorubicin: A New Therapeutic Strategy against Doxorubicin-Resistant Osteosarcoma.
abstract: Doxorubicin is one of the leading drugs for osteosarcoma standard chemotherapy. A total of 40% to 45% of high-grade osteosarcoma patients are unresponsive, or only partially responsive, to doxorubicin (Dox), due to the overexpression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). The aim of this work is to improve Dox-based regimens in resistant osteosarcomas. We used a chemically modified mitochondria-targeted Dox (mtDox) against Pgp-overexpressing osteosarcomas with increased resistance to Dox. Unlike Dox, mtDox accumulated at significant levels intracellularly, exerted cytotoxic activity, and induced necrotic and immunogenic cell death in Dox-resistant/Pgp-overexpressing cells, fully reproducing the activities exerted by anthracyclines in drug-sensitive tumors. mtDox reduced tumor growth and cell proliferation, increased apoptosis, primed tumor cells for recognition by the host immune system, and was less cardiotoxic than Dox in preclinical models of drug-resistant osteosarcoma. The increase in Dox resistance was paralleled by a progressive upregulation of mitochondrial metabolism. By widely modulating the expression of mitochondria-related genes, mtDox decreased mitochondrial biogenesis, the import of proteins and metabolites within mitochondria, mitochondrial metabolism, and the synthesis of ATP. These events were paralleled by increased reactive oxygen species production, mitochondrial depolarization, and mitochondria-dependent apoptosis in resistant osteosarcoma cells, where Dox was completely ineffective. We propose mtDox as a new effective agent with a safer toxicity profile compared with Dox that may be effective for the treatment of Dox-resistant/Pgp-positive osteosarcoma patients, who strongly need alternative and innovative treatment strategies. Mol Cancer Ther; 15(11); 2640-52. ©2016 AACR.
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Buondonno
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gazzano
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.|Department of Chemistry, Faculty of Arts and Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sae Rin
authors.initials: SR
authors.lastname: Jean
authors.affiliation: Human Genetics Foundation (HuGeF), Torino, Italy.|Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Audrito
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kopecka
authors.affiliation: Orthopaedic Rizzoli Institute, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, Bologna, Italy.
authors.forename: Marilù
authors.initials: M
authors.lastname: Fanelli
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Iris C
authors.initials: IC
authors.lastname: Salaroglio
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Costanzo
authors.initials: C
authors.lastname: Costamagna
authors.affiliation: Center for Research and Experimental Medicine (Ce.R.M.S.), San Giovanni Battista Hospital, Torino, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Roato
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Mungo
authors.affiliation: Orthopaedic Rizzoli Institute, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, Bologna, Italy.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Hattinger
authors.affiliation: Human Genetics Foundation (HuGeF), Torino, Italy.|Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Deaglio
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.|Department of Chemistry, Faculty of Arts and Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shana O
authors.initials: SO
authors.lastname: Kelley
authors.affiliation: Orthopaedic Rizzoli Institute, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, Bologna, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Serra
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy. chiara.riganti@unito.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Riganti
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D017382:Reactive Oxygen Species; D004317:Doxorubicin