Leukemia cells demonstrate a different metabolic perturbation provoked by 2-deoxyglucose

Miwa,Hiroshi; Shikami,Masato; Goto,Mineaki; Mizuno,Shohei; Takahashi,Miyuki; Tsunekawa-Imai,Norikazu; Ishikawa,Takamasa; Mizutani,Motonori; Horio,Tomohiro; Gotou,Mayuko; Yamamoto,Hidesuke; Wakabayashi,Motohiro; Watarai,Masaya; Hanamura,Ichiro; Imamura,Akira; Mihara,Hidetsugu; Nitta,Masakazu

doi:10.3892/or.2013.2299

May 2013 Volume 29 Issue 5

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May 2013 Volume 29 Issue 5

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Article

Leukemia cells demonstrate a different metabolic perturbation provoked by 2-deoxyglucose

Authors:
- Hiroshi Miwa
- Masato Shikami
- Mineaki Goto
- Shohei Mizuno
- Miyuki Takahashi
- Norikazu Tsunekawa-Imai
- Takamasa Ishikawa
- Motonori Mizutani
- Tomohiro Horio
- Mayuko Gotou
- Hidesuke Yamamoto
- Motohiro Wakabayashi
- Masaya Watarai
- Ichiro Hanamura
- Akira Imamura
- Hidetsugu Mihara
- Masakazu Nitta
View Affiliations / Copyright

Affiliations: Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan, Human Metabolome Technologies, Tsuruoka, Yamagata, Japan
Pages: 2053-2057
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Published online on: February 21, 2013

https://doi.org/10.3892/or.2013.2299
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Abstract

The shift in energy metabolism from oxidative phosphorylation to glycolysis can serve as a target for the inhibition of cancer growth. Here, we examined the metabolic changes induced by 2-deoxyglucose (2-DG), a glycolysis inhibitor, in leukemia cells by metabolome analysis. NB4 cells mainly utilized glucose as an energy source by glycolysis and oxidative phosphorylation in mitochondria, since metabolites in the glycolytic pathway and in the tricarboxylic acid (TCA) cycle were significantly decreased by 2-DG. In THP-1 cells, metabolites in the TCA cycle were not decreased to the same extent by 2-DG as in NB4 cells, which indicates that THP-1 utilizes energy sources other than glucose. TCA cycle metabolites in THP-1 cells may be derived from acetyl-CoA by fatty acid β-oxidation, which was supported by abundant detection of carnitine and acetylcarnitine in THP-1 cells. 2-DG treatment increased the levels of pentose phosphate pathway (PPP) metabolites and augmented the generation of NADPH by glucose-6-phosphate dehydrogenase. An increase in NADPH and upregulation of glutathione synthetase expression resulted in the increase in the reduced form of glutathione by 2-DG in NB4 cells. We demonstrated that a combination of 2-DG and inhibition of PPP by dehydroepiandrosterone (DHEA) effectively suppressed the growth of NB4 cells. The replenishment of the TCA cycle by fatty acid oxidation by carnitine palmitoyltransferase in THP-1 cells, treated by 2-DG, might be regulated by AMPK, as the combination of 2-DG and inhibition of AMPK by compound C potently suppressed the growth of THP-1 cells. Although 2-DG has been effective in preclinical and clinical studies, this treatment has not been fully explored due to concerns related to potential toxicities such as brain toxicity at high doses. We demonstrated that a combination of 2-DG and DHEA or compound C at a relatively low concentration effectively inhibits the growth of NB4 and THP-1 cells, respectively. These observations may aid in the identification of appropriate combinations of metabolic inhibitors at low concentrations which do not cause toxicities.

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Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Leukemia cells demonstrate a different metabolic perturbation provoked by 2-deoxyglucose

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