Research Papers:

Reprogramming of leukemic cell metabolism through the naphthoquinonic compound Quambalarine B

Karel Vališ _, Valéria Grobárová, Lucie Hernychová, Martina Bugáňová, Daniel Kavan, Martin Kalous, Jiří Černý, Eva Stodůlková, Marek Kuzma, Miroslav Flieger, Jan Černý and Petr Novák

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Oncotarget. 2017; 8:103137-103153. https://doi.org/10.18632/oncotarget.21663

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Karel Vališ1,2, Valéria Grobárová3, Lucie Hernychová1,3, Martina Bugáňová4,5, Daniel Kavan2,4, Martin Kalous3, Jiří Černý6, Eva Stodůlková4, Marek Kuzma4, Miroslav Flieger4, Jan Černý3 and Petr Novák1,2

1BIOCEV, Institute of Microbiology, v.v.i., The Czech Academy of Sciences, Vestec, Czech Republic

2Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic

3Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic

4Institute of Microbiology, v.v.i., The Czech Academy of Sciences, Prague, Czech Republic

5Faculty of Chemical Technology, University of Chemistry and Technology, Prague, Czech Republic

6BIOCEV, Institute of Biotechnology, v.v.i., The Czech Academy of Sciences, Vestec, Czech Republic

Correspondence to:

Karel Vališ, email: [email protected]

Petr Novák, email: [email protected]

Keywords: metabolism, leukemia, naphthoquinones, mitochondria, therapy

Received: July 14, 2017     Accepted: September 21, 2017     Published: October 07, 2017


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.

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PII: 21663