Mitochondria-targeted doxorubicin: A new therapeutic strategy against doxorubicin-resistant osteosarcoma

Ilaria Buondonno, Elena Gazzano, Sae Rin Jean, Valentina Audrito, Joanna Kopecka, Marilù Fanelli, Iris C. Salaroglio, Costanzo Costamagna, Ilaria Roato, Eleonora Mungo, Claudia M. Hattinger, Silvia Deaglio, Shana O. Kelley, Massimo Serra, Chiara Riganti*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2640-2652
Number of pages13
JournalMolecular cancer therapeutics
Issue number11
StatePublished - Nov 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Mitochondria-targeted doxorubicin: A new therapeutic strategy against doxorubicin-resistant osteosarcoma'. Together they form a unique fingerprint.

Cite this