Tags

Type your tag names separated by a space and hit enter

Mitochondria-Targeted Doxorubicin: A New Therapeutic Strategy against Doxorubicin-Resistant Osteosarcoma.
Mol Cancer Ther. 2016 11; 15(11):2640-2652.MC

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+Show Affiliations

Department of Oncology, University of Torino, Torino, Italy.Department of Oncology, University of Torino, Torino, Italy.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.Human Genetics Foundation (HuGeF), Torino, Italy. Department of Medical Sciences, University of Torino, Torino, Italy.Department of Oncology, University of Torino, Torino, Italy.Orthopaedic Rizzoli Institute, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, Bologna, Italy.Department of Oncology, University of Torino, Torino, Italy.Department of Oncology, University of Torino, Torino, Italy.Center for Research and Experimental Medicine (Ce.R.M.S.), San Giovanni Battista Hospital, Torino, Italy.Department of Oncology, University of Torino, Torino, Italy.Orthopaedic Rizzoli Institute, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, Bologna, Italy.Human Genetics Foundation (HuGeF), Torino, Italy. Department of Medical Sciences, University of Torino, Torino, Italy.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.Orthopaedic Rizzoli Institute, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, Bologna, Italy.Department of Oncology, University of Torino, Torino, Italy. chiara.riganti@unito.it.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27466354

Citation

Buondonno, Ilaria, et al. "Mitochondria-Targeted Doxorubicin: a New Therapeutic Strategy Against Doxorubicin-Resistant Osteosarcoma." Molecular Cancer Therapeutics, vol. 15, no. 11, 2016, pp. 2640-2652.
Buondonno I, Gazzano E, Jean SR, et al. Mitochondria-Targeted Doxorubicin: A New Therapeutic Strategy against Doxorubicin-Resistant Osteosarcoma. Mol Cancer Ther. 2016;15(11):2640-2652.
Buondonno, I., Gazzano, E., Jean, S. R., Audrito, V., Kopecka, J., Fanelli, M., Salaroglio, I. C., Costamagna, C., Roato, I., Mungo, E., Hattinger, C. M., Deaglio, S., Kelley, S. O., Serra, M., & Riganti, C. (2016). Mitochondria-Targeted Doxorubicin: A New Therapeutic Strategy against Doxorubicin-Resistant Osteosarcoma. Molecular Cancer Therapeutics, 15(11), 2640-2652.
Buondonno I, et al. Mitochondria-Targeted Doxorubicin: a New Therapeutic Strategy Against Doxorubicin-Resistant Osteosarcoma. Mol Cancer Ther. 2016;15(11):2640-2652. PubMed PMID: 27466354.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondria-Targeted Doxorubicin: A New Therapeutic Strategy against Doxorubicin-Resistant Osteosarcoma. AU - Buondonno,Ilaria, AU - Gazzano,Elena, AU - Jean,Sae Rin, AU - Audrito,Valentina, AU - Kopecka,Joanna, AU - Fanelli,Marilù, AU - Salaroglio,Iris C, AU - Costamagna,Costanzo, AU - Roato,Ilaria, AU - Mungo,Eleonora, AU - Hattinger,Claudia M, AU - Deaglio,Silvia, AU - Kelley,Shana O, AU - Serra,Massimo, AU - Riganti,Chiara, Y1 - 2016/07/27/ PY - 2016/02/01/received PY - 2016/06/23/accepted PY - 2016/11/4/pubmed PY - 2017/6/16/medline PY - 2016/7/29/entrez SP - 2640 EP - 2652 JF - Molecular cancer therapeutics JO - Mol. Cancer Ther. VL - 15 IS - 11 N2 - 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. SN - 1538-8514 UR - https://www.unboundmedicine.com/medline/citation/27466354/Mitochondria_Targeted_Doxorubicin:_A_New_Therapeutic_Strategy_against_Doxorubicin_Resistant_Osteosarcoma_ L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=27466354 DB - PRIME DP - Unbound Medicine ER -