Oncotarget

Research Papers:

NADH autofluorescence, a new metabolic biomarker for cancer stem cells: Identification of Vitamin C and CAPE as natural products targeting “stemness”

Gloria Bonuccelli, Ernestina Marianna De Francesco, Rianne de Boer, Herbert B. Tanowitz, Michael P. Lisanti _

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Oncotarget. 2017; 8:20667-20678. https://doi.org/10.18632/oncotarget.15400

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Abstract

Gloria Bonuccelli1, Ernestina Marianna De Francesco1,2, Rianne de Boer1, Herbert B. Tanowitz3 and Michael P. Lisanti4

1 The Paterson Building, University of Manchester, Withington, M20 4BX, United Kingdom

2 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, 87036, Italy

3 Departments of Pathology and Medicine, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

4 Translational Medicine, School of Environment and Life Sciences, Biomedical Research Centre, University of Salford, Greater Manchester, M5 4WT, United Kingdom

Correspondence to:

Michael P. Lisanti, email:

Gloria Bonuccelli, email:

Keywords: cancer stem-like cells; metabolic heterogeneity; metabolic cell fractionation; mitochondria; NADH

Received: January 10, 2017 Accepted: January 25, 2017 Published: February 16, 2017

Abstract

Here, 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.

Author Information

Gloria Bonuccelli

Ernestina Marianna De Francesco

Rianne de Boer

Herbert B. Tanowitz

Michael P. Lisanti
Primary Contact  _


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