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000125993 0247_ $$2doi$$a10.18632/oncotarget.2120
000125993 0247_ $$2pmid$$apmid:25015789
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000125993 1001_ $$0P:(DE-HGF)0$$aIsayev, Orkhan$$b0$$eFirst author
000125993 245__ $$aInhibition of glucose turnover by 3-bromopyruvate counteracts pancreatic cancer stem cell features and sensitizes cells to gemcitabine.
000125993 260__ $$a[S.l.]$$bImpact Journals LLC$$c2014
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000125993 520__ $$aAccording to the cancer stem cell (CSC) hypothesis, the aggressive growth and early metastasis of pancreatic ductal adenocarcinoma (PDA) is due to the activity of CSCs, which are not targeted by current therapies. Otto Warburg suggested that the growth of cancer cells is driven by a high glucose metabolism. Here, we investigated whether glycolysis inhibition targets CSCs and thus may enhance therapeutic efficacy. Four established and 3 primary PDA cell lines, non-malignant cells, and 3 patient-tumor-derived CSC-enriched spheroidal cultures were analyzed by glucose turnover measurements, MTT and ATP assays, flow cytometry of ALDH1 activity and annexin positivity, colony and spheroid formation, western blotting, electrophoretic mobility shift assay, xenotransplantation, and immunohistochemistry. The effect of siRNA-mediated inhibition of LDH-A and LDH-B was also investigated. The PDA cells exhibited a high glucose metabolism, and glucose withdrawal or LDH inhibition by siRNA prevented growth and colony formation. Treatment with the anti-glycolytic agent 3-bromopyruvate almost completely blocked cell viability, self-renewal potential, NF-κB binding activity, and stem cell-related signaling and reverted gemcitabine resistance. 3-bromopyruvate was less effective in weakly malignant PDA cells and did not affect non-malignant cells, predicting minimal side effects. 3-bromopyruvate inhibited in vivo tumor engraftment and growth on chicken eggs and mice and enhanced the efficacy of gemcitabine by influencing the expression of markers of proliferation, apoptosis, self-renewal, and metastasis. Most importantly, primary CSC-enriched spheroidal cultures were eliminated by 3-bromopyruvate. These findings propose that CSCs may be specifically dependent on a high glucose turnover and suggest 3-bromopyruvate for therapeutic intervention.
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000125993 650_7 $$2NLM Chemicals$$aAntimetabolites, Antineoplastic
000125993 650_7 $$2NLM Chemicals$$aBiomarkers, Tumor
000125993 650_7 $$2NLM Chemicals$$aIsoenzymes
000125993 650_7 $$2NLM Chemicals$$aPyruvates
000125993 650_7 $$00W860991D6$$2NLM Chemicals$$aDeoxycytidine
000125993 650_7 $$063JMV04GRK$$2NLM Chemicals$$abromopyruvate
000125993 650_7 $$0B76N6SBZ8R$$2NLM Chemicals$$agemcitabine
000125993 650_7 $$0EC 1.1.1.27$$2NLM Chemicals$$aL-Lactate Dehydrogenase
000125993 650_7 $$0IY9XDZ35W2$$2NLM Chemicals$$aGlucose
000125993 7001_ $$0P:(DE-HGF)0$$aRausch, Vanessa$$b1
000125993 7001_ $$0P:(DE-He78)bf58bfc5eb550025e7f1f64520b68feb$$aBauer, Nathalie$$b2$$udkfz
000125993 7001_ $$0P:(DE-He78)0144e4bf6eab6053de5a445069012063$$aLiu, Lizhen$$b3$$udkfz
000125993 7001_ $$0P:(DE-HGF)0$$aFan, Pei$$b4
000125993 7001_ $$0P:(DE-HGF)0$$aZhang, Yiyao$$b5
000125993 7001_ $$0P:(DE-HGF)0$$aGladkich, Jury$$b6
000125993 7001_ $$0P:(DE-He78)a4d7add6f8b4635d23ecdd700a5990af$$aNwaeburu, Clifford$$b7$$udkfz
000125993 7001_ $$0P:(DE-HGF)0$$aMattern, Jürgen$$b8
000125993 7001_ $$aMollenhauer, Martin$$b9
000125993 7001_ $$aRückert, Felix$$b10
000125993 7001_ $$aZach, Sebastian$$b11
000125993 7001_ $$0P:(DE-He78)13a0afba029f5f64dc18b25ef7499558$$aHaberkorn, Uwe$$b12$$udkfz
000125993 7001_ $$0P:(DE-HGF)0$$aGross, Wolfgang$$b13
000125993 7001_ $$0P:(DE-HGF)0$$aSchönsiegel, Frank$$b14
000125993 7001_ $$aBazhin, Alexandr V$$b15
000125993 7001_ $$0P:(DE-HGF)0$$aHerr, Ingrid$$b16$$eLast author
000125993 773__ $$0PERI:(DE-600)2560162-3$$a10.18632/oncotarget.2120$$gVol. 5, no. 13, p. 5177 - 5189$$n13$$p5177 - 5189$$tOncoTarget$$v5$$x1949-2553$$y2014
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