Inhibition of glucose turnover by 3-bromopyruvate counteracts pancreatic cancer stem cell features and sensitizes cells to gemcitabine
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Orkhan Isayev1,2,*, Vanessa Rausch1,2,*, Nathalie Bauer1,2, Li Liu1,2, Pei Fan1,2, Yiyao Zhang1,2, Jury Gladkich1,2, Clifford C. Nwaeburu1,2, Jürgen Mattern1,2, Martin Mollenhauer2, Felix Rückert3, Sebastian Zach3, Uwe Haberkorn4, Wolfgang Gross1,2, Frank Schönsiegel1,2, Alexandr V. Bazhin5 and Ingrid Herr1,2
1 Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
2 General-, Visceral- & Transplantation Surgery, Section Experimental Surgery, University of Heidelberg, Germany
3 Department of Surgery, University Hospital Mannheim, Germany
4 Department of Nuclear Medicine, University of Heidelberg, Germany
5 Department of General-, Visceral-, Transplantation-, Vascular- and Thoraxsurgery, University Hospital München - Großhadern, Germany
* These authors contributed equally to this work
Ingrid Herr, email:
Keywords: Pancreatic cancer, Cancer stem cells, Novel therapeutics, Warburg effect, 3-Bromopyruvate
Received: June 12, 2014 Accepted: June 13, 2014 Published: June 15, 2014
According to the cancer stem cell (CSC) hypothesis, the aggressive growth and early metastasis of pancreatic ductal adenocarcinoma (PDA) is due to the activity of CSCs, which are not targeted by current therapies. Otto Warburg suggested that the growth of cancer cells is driven by a high glucose metabolism. Here, we investigated whether glycolysis inhibition targets CSCs and thus may enhance therapeutic efficacy. Four established and 3 primary PDA cell lines, non-malignant cells, and 3 patient-tumor-derived CSC-enriched spheroidal cultures were analyzed by glucose turnover measurements, MTT and ATP assays, flow cytometry of ALDH1 activity and annexin positivity, colony and spheroid formation, western blotting, electrophoretic mobility shift assay, xenotransplantation, and immunohistochemistry. The effect of siRNA-mediated inhibition of LDH-A and LDH-B was also investigated. The PDA cells exhibited a high glucose metabolism, and glucose withdrawal or LDH inhibition by siRNA prevented growth and colony formation. Treatment with the anti-glycolytic agent 3-bromopyruvate almost completely blocked cell viability, self-renewal potential, NF-κB binding activity, and stem cell-related signaling and reverted gemcitabine resistance. 3-bromopyruvate was less effective in weakly malignant PDA cells and did not affect non-malignant cells, predicting minimal side effects. 3-bromopyruvate inhibited in vivo tumor engraftment and growth on chicken eggs and mice and enhanced the efficacy of gemcitabine by influencing the expression of markers of proliferation, apoptosis, self-renewal, and metastasis. Most importantly, primary CSC-enriched spheroidal cultures were eliminated by 3-bromopyruvate. These findings propose that CSCs may be specifically dependent on a high glucose turnover and suggest 3-bromopyruvate for therapeutic intervention.
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