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dc.contributor.authorBonuccelli, Gloria
dc.contributor.authorDe Francesco, Ernestina M
dc.contributor.authorde Boer, Rianne
dc.contributor.authorTanowitz, Herbert B
dc.contributor.authorLisanti, Michael P
dc.date.accessioned2017-03-16T11:21:59Z
dc.date.available2017-03-16T11:21:59Z
dc.date.issued2017-02-16
dc.identifier.citationNADH autofluorescence, a new metabolic biomarker for cancer stem cells: identification of vitamin C and CAPE as natural products targeting "stemness". 2017, Oncotargeten
dc.identifier.issn1949-2553
dc.identifier.pmid28223550
dc.identifier.doi10.18632/oncotarget.15400
dc.identifier.urihttp://hdl.handle.net/10541/620201
dc.description.abstractHere, we assembled a broad molecular "tool-kit" to interrogate the role of metabolic heterogeneity in the propagation of cancer stem-like cells (CSCs). First, we subjected MCF7 cells to "metabolic fractionation" by flow cytometry, using fluorescent mitochondrial probes to detect PCG1α activity, as well ROS and hydrogen-peroxide (H2O2) production; NADH levels were also monitored by auto-fluorescence. Then, the various cell populations were functionally assessed for "stem cell activity", using the mammosphere assay (3D-spheroids). Our results indicate that a sub-population of MCF7 cells, with increased PGC1α activity, high mitochondrial ROS/H2O2 production and high NADH levels, all form mammospheres with a higher efficiency. Thus, it appears that mitochondrial oxidative stress and the anti-oxidant response both contribute to the promotion of mitochondrial biogenesis and oxidative metabolism in CSCs. Further validation was provided by using specific inhibitors to target metabolic processes (the NAD+ salvage pathway, glycolysis, mitochondrial protein synthesis and OXPHOS), significantly reducing CSC propagation. As a consequence, we have now identified a variety of clinically-approved drugs (stiripentol), natural products (caffeic acid phenyl ester (CAPE), ascorbic acid, silibinin) and experimental pharmaceuticals (actinonin, FK866, 2-DG), that can be used to effectively inhibit CSC activity. We discuss the use of CAPE (derived from honey-bee propolis) and Vitamin C, as potential natural therapeutic modalities. In this context, Vitamin C was ~10 times more potent than 2-DG for the targeting of CSCs. Similarly, stiripentol was between 50 to 100 times more potent than 2-DG.
dc.language.isoenen
dc.rightsArchived with thanks to Oncotargeten
dc.titleNADH autofluorescence, a new metabolic biomarker for cancer stem cells: identification of vitamin C and CAPE as natural products targeting "stemness".en
dc.typeArticleen
dc.contributor.departmentThe Paterson Building, University of Manchester, Withington, United Kingdomen
dc.identifier.journalOncotargeten
refterms.dateFOA2018-12-17T14:53:00Z
html.description.abstractHere, we assembled a broad molecular "tool-kit" to interrogate the role of metabolic heterogeneity in the propagation of cancer stem-like cells (CSCs). First, we subjected MCF7 cells to "metabolic fractionation" by flow cytometry, using fluorescent mitochondrial probes to detect PCG1α activity, as well ROS and hydrogen-peroxide (H2O2) production; NADH levels were also monitored by auto-fluorescence. Then, the various cell populations were functionally assessed for "stem cell activity", using the mammosphere assay (3D-spheroids). Our results indicate that a sub-population of MCF7 cells, with increased PGC1α activity, high mitochondrial ROS/H2O2 production and high NADH levels, all form mammospheres with a higher efficiency. Thus, it appears that mitochondrial oxidative stress and the anti-oxidant response both contribute to the promotion of mitochondrial biogenesis and oxidative metabolism in CSCs. Further validation was provided by using specific inhibitors to target metabolic processes (the NAD+ salvage pathway, glycolysis, mitochondrial protein synthesis and OXPHOS), significantly reducing CSC propagation. As a consequence, we have now identified a variety of clinically-approved drugs (stiripentol), natural products (caffeic acid phenyl ester (CAPE), ascorbic acid, silibinin) and experimental pharmaceuticals (actinonin, FK866, 2-DG), that can be used to effectively inhibit CSC activity. We discuss the use of CAPE (derived from honey-bee propolis) and Vitamin C, as potential natural therapeutic modalities. In this context, Vitamin C was ~10 times more potent than 2-DG for the targeting of CSCs. Similarly, stiripentol was between 50 to 100 times more potent than 2-DG.


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