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

Doxorubicin is one of the leading drugs for osteosarcoma standard chemotherapy. 40-45% of high grade osteosarcoma patients are unresponsive, or only partially responsive, to doxorubicin, due to the overexpression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). The aim of this work is to improve doxorubicin-based regimens in resistant osteosarcomas. We used a chemically modified mitochondria-targeted doxorubicin (mtDox) against Pgp-overexpressing osteosarcomas with increased resistance to doxorubicin. Unlike doxorubicin, mtDox accumulated at significant levels intracellularly, exerted cytotoxic activity, induced necrotic and immunogenic cell death in doxorubicin-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 the recognition by the host immune system and was less cardiotoxic than doxorubicin in pre-clinical models of drug-resistant osteosarcoma. The increase in doxorubicin 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 doxorubicin was completely ineffective. We propose mtDox as a new effective agent with a safer toxicity profile compared to doxorubicin that may be effective for the treatment of doxorubicin-resistant/Pgp-positive osteosarcoma patients, who strongly need alternative and innovative treatment strategies.