Breast cancer growth and proliferation is suppressed by the mitochondrial targeted furazano[3,4-b]pyrazine BAM15.

Autor:	Zunica ERM; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA, 70808, USA.; Department of Nutrition, Case Western Reserve University, Cleveland, OH, 44109, USA.; Clinical Oncology and Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA., Axelrod CL; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA, 70808, USA.; Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA., Cho E; School of Kinesiology, Louisiana State University, Baton Rouge, LA, USA., Spielmann G; School of Kinesiology, Louisiana State University, Baton Rouge, LA, USA., Davuluri G; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA, 70808, USA.; Sarcopenia and Malnutrition Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA., Alexopoulos SJ; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, 2052, Australia., Beretta M; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, 2052, Australia., Hoehn KL; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, 2052, Australia., Dantas WS; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA, 70808, USA., Stadler K; Department of Oxidative Stress and Disease, Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA., King WT; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA, 70808, USA.; Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA., Pergola K; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA, 70808, USA.; Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA., Irving BA; School of Kinesiology, Louisiana State University, Baton Rouge, LA, USA., Langohr IM; Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, LA, 70803, USA., Yang S; Department of Biostatistics, Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA., Hoppel CL; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA, 70808, USA.; Department of Pharmacology, Case Western Reserve University, Cleveland, OH, 44109, USA., Gilmore LA; Clinical Oncology and Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA.; Department of Clinical Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Kirwan JP; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA, 70808, USA. john.kirwan@pbrc.edu.; Department of Nutrition, Case Western Reserve University, Cleveland, OH, 44109, USA. john.kirwan@pbrc.edu.; Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA. john.kirwan@pbrc.edu.
Jazyk:	angličtina
Zdroj:	Cancer & metabolism [Cancer Metab] 2021 Oct 09; Vol. 9 (1), pp. 36. Date of Electronic Publication: 2021 Oct 09.
DOI:	10.1186/s40170-021-00274-5
Abstrakt:	Background: Enhanced 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. Methods: The 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. Results: BAM15 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. Conclusions: Collectively, 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. (© 2021. The Author(s).)
Databáze:	MEDLINE
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