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.

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…230 In a study exploring resistance mechanisms, Buondonno et al (from University of Torino, Torino, Italy) documented that treating osteosarcoma cells that overexpress ATP binding cassette subfamily B member 1 (ABCB1) -a plasma membrane transporter that actively extrudes several chemotherapeutics including doxorubicin -with mitochondria-targeted doxorubicin overcomes chemoresistance to restore ICD and associated immune responses in vivo. 231 Finally, Shalapour and co-authors (from University of California San Diego, San Diego, CA, USA) reported that B cells producing class A immunoglobulins (IgAs), IL10 and PD-L1 in a TGFB1-dependent fashion act as immunosuppressive plasmocytes and prevent oxaliplatin-driven tumor rejection in different murine models of prostate cancer. 232 Thounaojam and colleagues (from Meharry Medical College, Nashville, TN, USA) found that bortezomib suppresses the growth of various solid tumors by upregulating the expression of various components of the Notch signaling pathway in lymphoid tissues including CD8 C CTLs, resulting in increased cytotoxic functions.…”

Teaching the basics of cancer metabolism: Developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism

“…Mitochondria-targeted compounds can potentially increase the therapeutic window of chemotherapeutics. Emerging research suggests that selective targeting of anticancer drugs ( cis -platin and doxorubicin) helps overcome the drug resistance [78], [79]. This is an exciting time for cancer cell metabolism research that is becoming increasingly relevant in the clinical setting [80], [81].…”

Bortezomib sensitizes human osteosarcoma cells to adriamycin‐induced apoptosis through ROS‐dependent activation of p‐eIF2α/ATF4/CHOP axis

“…Moreover, outcome of adriamycin chemotherapy in osteosarcoma remains unsatisfactory because a significant number of patients will still relapse and the cure rate has no further improvements in terms of survival in recent decades . Therefore, research of new powerful chemotherapy regimens are always hot spot and of great importance in the field of osteosarcoma therapy . It is particularly urgent to provide better chemotherapies which could dramatically raise the efficacy of adriamycin for osteosarcoma patients.…”