title: Mitochondria-targeted drugs synergize with 2-deoxyglucose to trigger breast cancer cell death.
abstract: Cancer cells are long known to exhibit increased aerobic glycolysis, but glycolytic inhibition has not offered a viable chemotherapeutic strategy in part because of the systemic toxicity of antiglycolytic agents. However, recent studies suggest that a combined inhibition of glycolysis and mitochondrial function may help overcome this issue. In this study, we investigated the chemotherapeutic efficacies of mitochondria-targeted drugs (MTD) in combination with 2-deoxy-d-glucose (2-DG), a compound that inhibits glycolysis. Using the MTDs, termed Mito-CP and Mito-Q, we evaluated relative cytotoxic effects and mitochondrial bioenergetic changes in vitro. Interestingly, both Mito-CP and Mito-Q synergized with 2-DG to decrease ATP levels in two cell lines. However, with time, the cellular bioenergetic function and clonogenic survival were largely restored in some cells. In a xenograft model of human breast cancer, combined treatment of Mito-CP and 2-DG led to significant tumor regression in the absence of significant morphologic changes in kidney, liver, or heart. Collectively, our findings suggest that dual targeting of mitochondrial bioenergetic metabolism with MTDs and glycolytic inhibitors such as 2-DG may offer a promising chemotherapeutic strategy.
authors.affiliation: Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Cheng
authors.forename: Jacek
authors.initials: J
authors.lastname: Zielonka
authors.forename: Brian P
authors.initials: BP
authors.lastname: Dranka
authors.forename: Donna
authors.initials: D
authors.lastname: McAllister
authors.forename: A Craig
authors.initials: AC
authors.lastname: Mackinnon
authors.forename: Joy
authors.initials: J
authors.lastname: Joseph
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D014451:Ubiquinone / Q000494:pharmacology / Q000031:analogs & derivatives; D023041:Xenograft Model Antitumor Assays
chemical_list: D000963:Antimetabolites; D003497:Cyclic N-Oxides; D009943:Organophosphorus Compounds; C571715:mito-carboxy proxyl; D014451:Ubiquinone; C429014:mitoquinone; D003847:Deoxyglucose