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      Mitochondria-centric bioenergetic characteristics in cancer stem-like cells

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          Abstract

          Metabolic and genotoxic stresses that arise during tumor progression and anti-cancer treatment, respectively, can impose a selective pressure to promote cancer evolution in the tumor microenvironment. This process ultimately selects for the most “fit” clones, which generally have a cancer stem cell like phenotype with features of drug resistance, epithelial-mesenchymal transition, invasiveness, and high metastatic potential. From a bioenergetics perspective, these cancer stem-like cells (CSCs) exhibit mitochondria-centric energy metabolism and are capable of opportunistically utilizing available nutrients such as fatty acids to generate ATP and other metabolic substances, providing a selective advantage for their survival in an impermissible environment and metabolic context. Thus, diverse therapeutic strategies are needed to efficiently tackle these CSCs and eliminate their advantage. Here, we review the metabolic and bioenergetic characteristics and vulnerabilities specific to CSCs, which can provide an unprecedented opportunity to curb CSC-driven cancer mortality rates. We particularly focus on the potential of a CSC bioenergetics-targeted strategy as a versatile therapeutic component of treatment modalities applicable to most cancer types. A cancer bioenergetics-targeted strategy can expand the inventory of combinatorial regimens in the current anti-cancer armamentarium.

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          Evolutionary dynamics of carcinogenesis and why targeted therapy does not work.

          All malignant cancers, whether inherited or sporadic, are fundamentally governed by Darwinian dynamics. The process of carcinogenesis requires genetic instability and highly selective local microenvironments, the combination of which promotes somatic evolution. These microenvironmental forces, specifically hypoxia, acidosis and reactive oxygen species, are not only highly selective, but are also able to induce genetic instability. As a result, malignant cancers are dynamically evolving clades of cells living in distinct microhabitats that almost certainly ensure the emergence of therapy-resistant populations. Cytotoxic cancer therapies also impose intense evolutionary selection pressures on the surviving cells and thus increase the evolutionary rate. Importantly, the principles of Darwinian dynamics also embody fundamental principles that can illuminate strategies for the successful management of cancer.
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            Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer

            Expression of the oncogenic transcription factor MYC is disproportionately elevated in triple-negative breast cancer (TNBC) compared to estrogen, progesterone and human epidermal growth factor 2 receptor-positive (RP) breast tumors 1,2 . We and others have shown that MYC alters metabolism during tumorigenesis 3,4 . However, the role of MYC in TNBC metabolism remains largely unexplored. We hypothesized that MYC-dependent metabolic dysregulation is essential for MYC-overexpressing (MO) TNBC and may thus identify novel therapeutic targets for this clinically challenging subset of breast cancer. Using a targeted metabolomics approach, we identified fatty acid oxidation (FAO) intermediates as being dramatically upregulated in a MYC-driven model of TNBC. A lipid metabolism gene signature was identified in patients with TNBC from The Cancer Genome Atlas (TCGA) database and multiple other clinical datasets, implicating FAO as a dysregulated pathway critical for TNBC metabolism. We find that MO-TNBC displays increased bioenergetic reliance upon fatty acid oxidation (FAO), and that pharmacologic inhibition of FAO catastrophically decreases energy metabolism of MO-TNBC, blocks growth of a MYC-driven transgenic TNBC model and that of MO-TNBC patient-derived xenografts. Our results demonstrate that inhibition of FAO is a novel therapeutic strategy against MO-TNBC.
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              Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease

              Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of “stemness”, independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point – a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known “side-effect”, which could be harnessed instead as a “therapeutic effect”. Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.
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                Author and article information

                Contributors
                JHCHEONG@yuhs.ac
                Journal
                Arch Pharm Res
                Arch. Pharm. Res
                Archives of Pharmacal Research
                Pharmaceutical Society of Korea (Seoul )
                0253-6269
                15 February 2019
                15 February 2019
                2019
                : 42
                : 2
                : 113-127
                Affiliations
                [1 ]ISNI 0000 0004 0470 5454, GRID grid.15444.30, Yonsei University College of Medicine, ; Seoul, Korea
                [2 ]ISNI 0000 0004 0470 5454, GRID grid.15444.30, Department of Surgery, Yonsei University Health System, , Yonsei University College of Medicine, ; 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752 Korea
                [3 ]ISNI 0000 0004 0470 5454, GRID grid.15444.30, Yonsei Biomedical Research Institute, , Yonsei University College of Medicine, ; Seoul, Korea
                [4 ]ISNI 0000 0004 0470 5454, GRID grid.15444.30, Brain Korea 21 PLUS Project for Medical Science, , Yonsei University College of Medicine, ; Seoul, Korea
                [5 ]ISNI 0000 0004 0470 5454, GRID grid.15444.30, Department of Biochemistry & Molecular Biology, , Yonsei University College of Medicine, ; Seoul, Korea
                [6 ]ISNI 0000 0004 0470 5454, GRID grid.15444.30, Department of Biomedical Systems Informatics, , Yonsei University College of Medicine, ; Seoul, Korea
                Article
                1127
                10.1007/s12272-019-01127-y
                6399179
                30771209
                bf246731-bb9d-4c4b-948e-6bceff227dbc
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 21 November 2018
                : 28 January 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003625, Ministry of Health and Welfare;
                Award ID: 1020390
                Award ID: 1320360
                Award Recipient :
                Funded by: National Research Fund, Republic of Korea
                Award ID: NRF-2017R1D1A1B03032553
                Award Recipient :
                Funded by: Yonsei University College of Medicine
                Award ID: 6-2007-0095
                Award ID: 6-2008-0193
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Pharmaceutical Society of Korea 2019

                bioenergetics,cancer metabolism,cancer evolution,cancer stem cell,mitochondria,fatty acid oxidation,β-oxidation

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