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Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo

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Abstract

The glycolytic phenotype is a widespread phenomenon in solid cancer forms, including breast cancer. Dichloroacetate (DCA) has recently been proposed as a novel and relatively non-toxic anti-cancer agent that can reverse the glycolytic phenotype in cancer cells through the inhibition of pyruvate dehydrogenase kinase. We have examined the effect of DCA against breast cancer cells, including in a highly metastatic in vivo model. The growth of several breast cancer cell lines was found to be inhibited by DCA in vitro. Further examination of 13762 MAT rat mammary adenocarcinoma cells found that reversal of the glycolytic phenotype by DCA correlated with the inhibition of proliferation without any increase in cell death. This was despite a small but significant increase in caspase 3/7 activity, which may sensitize cancer cells to other apoptotic triggers. In vivo, DCA caused a 58% reduction in the number of lung metastases observed macroscopically after injection of 13762 MAT cells into the tail vein of rats (P = 0.0001, n ≥ 9 per group). These results demonstrate that DCA has anti-proliferative properties in addition to pro-apoptotic properties, and can be effective against highly metastatic disease in vivo, highlighting its potential for clinical use.

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Acknowledgments

This research was supported by a grant from the National Breast Cancer Foundation Australia, and by NHMRC 366787 R.D. Wright Career Development Award.

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Authors and Affiliations

  1. Molecular Genetics Group, John Curtin School of Medical Research, Australian National University, P.O. Box 334, Canberra, 2601, Australia

    Ramon C. Sun, Philip G. Board & Anneke C. Blackburn

  2. Department of Anatomical Pathology, Canberra Hospital and Australian National University Medical School, Woden, ACT 2606, Australia

    Mitali Fadia & Jane E. Dahlstrom

  3. Cancer and Vascular Biology Group, John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia

    Christopher R. Parish

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  1. Ramon C. Sun
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  2. Mitali Fadia
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  3. Jane E. Dahlstrom
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  4. Christopher R. Parish
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  5. Philip G. Board
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  6. Anneke C. Blackburn
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Correspondence to Anneke C. Blackburn.

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Sun, R.C., Fadia, M., Dahlstrom, J.E. et al. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 120, 253–260 (2010). https://doi.org/10.1007/s10549-009-0435-9

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  • DOI: https://doi.org/10.1007/s10549-009-0435-9

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