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Oncotarget. 2017 Oct 7;8(61):103137-103153. doi: 10.18632/oncotarget.21663. eCollection 2017 Nov 28.

Reprogramming of leukemic cell metabolism through the naphthoquinonic compound Quambalarine B.

Author information

1
BIOCEV, Institute of Microbiology, v.v.i., The Czech Academy of Sciences, Vestec, Czech Republic.
2
Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.
3
Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic.
4
Institute of Microbiology, v.v.i., The Czech Academy of Sciences, Prague, Czech Republic.
5
Faculty of Chemical Technology, University of Chemistry and Technology, Prague, Czech Republic.
6
BIOCEV, Institute of Biotechnology, v.v.i., The Czech Academy of Sciences, Vestec, Czech Republic.

Abstract

Abnormalities in cancer metabolism represent potential targets for cancer therapy. We have recently identified a natural compound Quambalarine B (QB), which inhibits proliferation of several leukemic cell lines followed by cell death. We have predicted ubiquinone binding sites of mitochondrial respiratory complexes as potential molecular targets of QB in leukemia cells. Hence, we tracked the effect of QB on leukemia metabolism by applying several omics and biochemical techniques. We have confirmed the inhibition of respiratory complexes by QB and found an increase in the intracellular AMP levels together with respiratory substrates. Inhibition of mitochondrial respiration by QB triggered reprogramming of leukemic cell metabolism involving disproportions in glycolytic flux, inhibition of proteins O-glycosylation, stimulation of glycine synthesis pathway, and pyruvate kinase activity, followed by an increase in pyruvate and a decrease in lactate levels. Inhibition of mitochondrial complex I by QB suppressed folate metabolism as determined by a decrease in formate production. We have also observed an increase in cellular levels of several amino acids except for aspartate, indicating the dependence of Jurkat (T-ALL) cells on aspartate synthesis. These results indicate blockade of mitochondrial complex I and II activity by QB and reduction in aspartate and folate metabolism as therapeutic targets in T-ALL cells. Anti-cancer activity of QB was also confirmed during in vivo studies, suggesting the therapeutic potential of this natural compound.

KEYWORDS:

leukemia; metabolism; mitochondria; naphthoquinones; therapy

Conflict of interest statement

CONFLICTS OF INTEREST Authors disclose no conflicts of interest.

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