title: Leukemia cells demonstrate a different metabolic perturbation provoked by 2-deoxyglucose.
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.
authors: Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan. hmiwa@aichi-med-u.ac.jp
authors: Hiroshi
authors: H
authors: Miwa
authors: Masato
authors: M
authors: Shikami
authors: Mineaki
authors: M
authors: Goto
authors: Shohei
authors: S
authors: Mizuno
authors: Miyuki
authors: M
authors: Takahashi
authors: Norikazu
authors: N
authors: Tsunekawa-Imai
authors: Takamasa
authors: T
authors: Ishikawa
authors: Motonori
authors: M
authors: Mizutani
authors: Tomohiro
authors: T
authors: Horio
authors: Mayuko
authors: M
authors: Gotou
authors: Hidesuke
authors: H
authors: Yamamoto
authors: Motohiro
authors: M
authors: Wakabayashi
authors: Masaya
authors: M
authors: Watarai
authors: Ichiro
authors: I
authors: Hanamura
authors: Akira
authors: A
authors: Imamura
authors: Hidetsugu
authors: H
authors: Mihara
authors: Masakazu
authors: M
authors: Nitta
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000105:Acetyl Coenzyme A / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D055442:Metabolome / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010427:Pentose Phosphate Pathway / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D005227:Fatty Acids; D011720:Pyrazoles; D011743:Pyrimidines; C516138:dorsomorphin; D003687:Dehydroepiandrosterone; D009249:NADP; D000105:Acetyl Coenzyme A; D003847:Deoxyglucose; D005954:Glucosephosphate Dehydrogenase; D002334:Carnitine O-Palmitoyltransferase; D055372:AMP-Activated Protein Kinases; D005978:Glutathione; D005947:Glucose