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, 108 8: 1624-1633. doi:10.1038/bjc.2013.120


Author Sanchez, W. Y.
McGee, S. L.
Connor, T.
Mottram, B.
Wilkinson, A.
Whitehead, J. P.
Vuckovic, S.
Catley, L.
Title Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib
Journal name British Journal of Cancer   Check publisher's open access policy
ISSN 0007-0920
1532-1827
Publication date 2013-04
Year available 2013
Sub-type Article (original research)
DOI 10.1038/bjc.2013.120
Open Access Status DOI
Volume 108
Issue 8
Start page 1624
End page 1633
Total pages 10
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2014
Language eng
Formatted abstract
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 G 0/1 and G 2 M 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
 
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