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 due to 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 (MTDs) 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 morphological 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.

Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

“…An enhanced antioxidant capacity allows cancer cells to not a universal finding, and mitochondrial respiration impairment is not a fixed feature of cancer cells [41] . Although the glycolytic inhibitors targeting the Warburg effect have been investigated in various cancer types, the glycolytic inhibitors with the exception of 3-BP (a lactate analog) [18,19, , 3-BrOP (a 3-bromopyruvate derivative) [71][72][73][74] , and dichloroacetate (DCA) have demonstrated low efficacy in arresting tumor growth when used alone [99] ; these inhibitors include 2-deoxy-D-glucose (a glucose analog) [70,[100][101][102][103][104][105][106][107][108][109][110][111][112] , lonidamine (a derivative of indazole-3-carboxylic acid) [113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132] , methyl jasmonate on HK , 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one on PFK [162]…”

Glycolysis Inhibition Sensitizes Non–Small Cell Lung Cancer with T790M Mutation to Irreversible EGFR Inhibitors via Translational Suppression of Mcl-1 by AMPK Activation

“…Nonetheless, combined treatment with 2DG and afatinib in the in vivo xenograft model showed more potent antitumor activity than that in in vitro. Although cancer cells exhibit increased glycolysis and depend more on this pathway for ATP generation, the inhibition of glycolysis alone is not sufficient to effectively kill the malignant cells, like monotherapy with glycolysis inhibitors including 2DG do not show antitumor activity in in vivo xenograft studies (17,42). It has been suggested that ATP depletion should reach certain thresholds to trigger cell death by apoptosis or necrosis (43).…”

Bioenergetic properties of human sarcoma cells help define sensitivity to metabolic inhibitors

“…9 Additionally, several recent studies have shown that simultaneous inhibition of glycolysis and mitochondrial respiration can act synergistically to reduce tumor cell survival in vitro and in vivo. [12][13][14] With respect to sarcomas, 2-DG induces apoptosis in human aRMS, but not eRMS, cell lines and inhibits osteosarcoma tumor growth (in combination with doxorubicin) and metastasis, although the mechanism and contribution of effects on cellular bioenergetics are not well-characterized. 5,15,16 Here, we describe the cellular bioenergetics of a panel of human RMS and osteosarcoma cell lines and examine the relationships between bioenergetic properties and sensitivity to metabolic inhibitors.…”