Dichloroacetate reverses the hypoxic adaptation to bevacizumab and enhances its antitumor effects in mouse xenografts

Krishan Kumar, Simon Wigfield, Harriet E. Gee, Cecilia M. Devlin, Dean Singleton, Ji Liang Li, Francesca Buffa, Melanie Huffman, Anthony L. Sinn, Jayne Silver, Helen Turley, Russell Leek, Adrian L. Harris, Mircea Ivan

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Abstract

Inhibition of vascular endothelial growth factor increases response rates to chemotherapy and progression-free survival in glioblastoma. However, resistance invariably occurs, prompting the urgent need for identification of synergizing agents. One possible strategy is to understand tumor adaptation to microenvironmental changes induced by antiangiogenic drugs and test agents that exploit this process. We used an in vivo glioblastoma-derived xenograft model of tumor escape in presence of continuous treatment with bevacizumab. U87-MG or U118-MG cells were subcutaneously implanted into either BALB/c SCID or athymic nude mice. Bevacizumab was given by intraperitoneal injection every 3 days (2.5 mg/kg/dose) and/or dichloroacetate (DCA) was administered by oral gavage twice daily (50 mg/kg/dose) when tumor volumes reached 0.3 cm3 and continued until tumors reached approximately 1.5-2.0 cm3. Microarray analysis of resistant U87 tumors revealed coordinated changes at the level of metabolic genes, in particular, a widening gap between glycolysis and mitochondrial respiration. There was a highly significant difference between U87-MG-implanted athymic nude mice 1 week after drug treatment. By 2 weeks of treatment, bevacizumab and DCA together dramatically blocked tumor growth compared to either drug alone. Similar results were seen in athymic nude mice implanted with U118-MG cells. We demonstrate for the first time that reversal of the bevacizumab-induced shift in metabolism using DCA is detrimental to neoplastic growth in vivo. As DCA is viewed as a promising agent targeting tumor metabolism, our data establish the timely proof of concept that combining it with antiangiogenic therapy represents a potent antineoplastic strategy.

Original languageEnglish (US)
Pages (from-to)749-758
Number of pages10
JournalJournal of Molecular Medicine
Volume91
Issue number6
DOIs
StatePublished - Jun 1 2013

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Keywords

  • Bevacizumab
  • Dichloroacetate
  • Glycolysis
  • Hypoxia
  • Oxidative phosphorylation

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

Cite this

Kumar, K., Wigfield, S., Gee, H. E., Devlin, C. M., Singleton, D., Li, J. L., Buffa, F., Huffman, M., Sinn, A. L., Silver, J., Turley, H., Leek, R., Harris, A. L., & Ivan, M. (2013). Dichloroacetate reverses the hypoxic adaptation to bevacizumab and enhances its antitumor effects in mouse xenografts. Journal of Molecular Medicine, 91(6), 749-758. https://doi.org/10.1007/s00109-013-0996-2