Abstract

BackgroundEnhanced metabolic plasticity and diversification of energy production is a hallmark of highly proliferative breast cancers. This contributes to poor pharmacotherapy efficacy, recurrence, and metastases. We have previously identified a mitochondrial-targeted furazano[3,4-b]pyrazine named BAM15 that selectively reduces bioenergetic coupling efficiency and is orally available. Here, we evaluated the antineoplastic properties of uncoupling oxidative phosphorylation from ATP production in breast cancer using BAM15.MethodsThe anticancer effects of BAM15 were evaluated in human triple-negative MDA-MB-231 and murine luminal B, ERα-negative EO771 cells as well as in an orthotopic allograft model of highly proliferative mammary cancer in mice fed a standard or high fat diet (HFD). Untargeted transcriptomic profiling of MDA-MB-231 cells was conducted after 16-h exposure to BAM15. Additionally, oxidative phosphorylation and electron transfer capacity was determined in permeabilized cells and excised tumor homogenates after treatment with BAM15.ResultsBAM15 increased proton leak and over time, diminished cell proliferation, migration, and ATP production in both MDA-MB-231 and EO771 cells. Additionally, BAM15 decreased mitochondrial membrane potential, while inducing apoptosis and reactive oxygen species accumulation in MDA-MB-231 and EO771 cells. Untargeted transcriptomic profiling of MDA-MB-231 cells further revealed inhibition of signatures associated with cell survival and energy production by BAM15. In lean mice, BAM15 lowered body weight independent of food intake and slowed tumor progression compared to vehicle-treated controls. In HFD mice, BAM15 reduced tumor growth relative to vehicle and calorie-restricted weight-matched controls mediated in part by impaired cell proliferation, mitochondrial respiratory function, and ATP production. LC-MS/MS profiling of plasma and tissues from BAM15-treated animals revealed distribution of BAM15 in adipose, liver, and tumor tissue with low abundance in skeletal muscle.ConclusionsCollectively, these data indicate that mitochondrial uncoupling may be an effective strategy to limit proliferation of aggressive forms of breast cancer. More broadly, these findings highlight the metabolic vulnerabilities of highly proliferative breast cancers which may be leveraged in overcoming poor responsiveness to existing therapies.

Highlights

  • Breast cancer is a highly prevalent and heterogeneous malignancy with more than 275,000 new cases diagnosed annually [1]

  • We found that BAM15 resulted in a dose-dependent inhibition of proliferation in MDAMB-231 and EO771 cells compared to the vehicle (Veh) (Fig. 1A, B)

  • We found that BAM15 resulted in a dose-dependent inhibition of cell migration of both MDA-MB-231 and EO771 cells (Fig. 1C, D)

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Summary

Introduction

Breast cancer is a highly prevalent and heterogeneous malignancy with more than 275,000 new cases diagnosed annually [1]. Mortality is attributable to the aggressive, more recurrent, and highly metastatic forms, such as triple-negative (TNBC) and estrogen receptor (ER)-negative breast cancer, which respond poorly to currently available targeted drug regimens [2,3,4,5,6,7]. Comorbidities such as obesity worsen clinical prognosis and exacerbate resistance to chemotherapy [8,9,10,11,12,13,14,15,16,17]. We evaluated the antineoplastic properties of uncoupling oxidative phosphorylation from ATP production in breast cancer using BAM15

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