Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib

Sanchez, W. Y., McGee, S. L., Connor, T., Mottram, B., Wilkinson, A., Whitehead, J. P., Vuckovic, S. and Catley, L. 2013, Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib, British journal of cancer, vol. 108, no. 8, pp. 1624-1633.

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Title Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib
Author(s) Sanchez, W. Y.
McGee, S. L.
Connor, T.
Mottram, B.
Wilkinson, A.
Whitehead, J. P.
Vuckovic, S.
Catley, L.
Journal name British journal of cancer
Volume number 108
Issue number 8
Start page 1624
End page 1633
Total pages 12
Publisher Nature Publishing Group
Place of publication London, England
Publication date 2013
ISSN 0007-0920
1532-1827
Keyword(s) multiple myeloma
dichloroacetate
aerobic glycolysis
Summary Background:
Dichloroacetate (DCA), through the inhibition of aerobic glycolysis (the ‘Warburg effect’) and promotion of pyruvate oxidation, induces growth reduction in many tumours and is now undergoing several clinical trials. If aerobic glycolysis is active in multiple myeloma (MM) cells, it can be potentially targeted by DCA to induce myeloma growth inhibition.

Methods:
Representative multiple myeloma cell lines and a myeloma-bearing mice were treated with DCA, alone and in combination with bortezomib.

Results:
We found that aerobic glycolysis occurs in approximately half of MM cell lines examined, producing on average 1.86-fold more lactate than phorbol myristate acetate stimulated-peripheral blood mononuclear cells and is associated with low-oxidative capacity. Lower doses of DCA (5–10 mM) suppressed aerobic glycolysis and improved cellular respiration that was associated with activation of the pyruvate dehydrogenase complex. Higher doses of DCA (10–25 mM) induced superoxide production, apoptosis, suppressed proliferation with a G0/1 and G2M phase arrest in MM cell lines. In addition, DCA increased MM cell line sensitivity to bortezomib, and combinatorial treatment of both agents improved the survival of myeloma-bearing mice.

Conclusion:
Myeloma cells display aerobic glycolysis and DCA may complement clinically used MM therapies to inhibit disease progression.
Language eng
Field of Research 111201 Cancer Cell Biology
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2013, Nature Publishing Group
Persistent URL http://hdl.handle.net/10536/DRO/DU:30060440

Document type: Journal Article
Collection: School of Medicine
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