PMID- 27538376
OWN - NLM
STAT- MEDLINE
DCOM- 20171103
LR  - 20180917
IS  - 0304-4165 (Print)
IS  - 0304-4165 (Linking)
VI  - 1861
IP  - 1 Pt A
DP  - 2017 Jan
TI  - Assessment of the low inhibitory specificity of oxamate, aminooxyacetate and 
      dichloroacetate on cancer energy metabolism.
PG  - 3221-3236
LID - S0304-4165(16)30287-2 [pii]
LID - 10.1016/j.bbagen.2016.08.006 [doi]
AB  - BACKGROUND: Exceedingly high therapeutic/experimental doses of metabolic drugs 
      such as oxamate, aminooxyacetate (AOA) and dichloroacetate (DCA) are required to 
      diminish growth, glycolysis and oxidative phosphorylation (OxPhos) of different 
      cancer cells. To identify the mechanisms of action of these drugs on cancer 
      energy metabolism, a systematic analysis of their specificities was undertaken. 
      METHODS: Hepatocarcinoma AS-30D cells were treated with the inhibitors and 
      glycolysis and OxPhos enzyme activities, metabolites and fluxes were analyzed. 
      Kinetic modeling of glycolysis was used to identify the regulatory mechanisms. 
      RESULTS: Oxamate (i) not only inhibited LDH, but also PYK and ENO activities 
      inducing an increase in the cytosolic NAD(P)H, Fru1,6BP and DHAP levels in AS-30D 
      cells; (ii) it slightly inhibited HPI, ALD and Glc6PDH; and (iii) it inhibited 
      pyruvate-driven OxPhos in isolated heart mitochondria. AOA (i) strongly inhibited 
      both AAT and AlaT, and 2-OGDH and glutamate-driven OxPhos; and (ii) moderately 
      affected GAPDH and TPI. DCA slightly affected pyruvate-driven OxPhos and Glc6PDH. 
      Kinetic modeling of cancer glycolysis revealed that oxamate inhibition of LDH, 
      PYK and ENO was insufficient to achieve glycolysis flux inhibition. To do so, HK, 
      HPI, TPI and GAPDH have to be also inhibited by the accumulated Fru1,6BP and DHAP 
      induced by oxamate. CONCLUSION: Oxamate, AOA, and DCA are not specific drugs 
      since they inhibit several enzymes/transporters of the glycolytic and OxPhos 
      pathways through direct interaction or indirect mechanisms. GENERAL SIGNIFICANCE: 
      These data explain why oxamate or AOA, through their multisite inhibitory actions 
      on glycolysis or OxPhos, may be able to decrease the proliferation of cancer 
      cells.
CI  - Copyright A(c) 2016 Elsevier B.V. All rights reserved.
FAU - Moreno-Sanchez, Rafael
AU  - Moreno-Sanchez R
AD  - Instituto Nacional de Cardiologia, Departamento de Bioquimica, Tlalpan D.F. 
      14080, Mexico. Electronic address: rafael.moreno@cardiologia.org.mx.
FAU - Marin-Hernandez, Alvaro
AU  - Marin-Hernandez A
AD  - Instituto Nacional de Cardiologia, Departamento de Bioquimica, Tlalpan D.F. 
      14080, Mexico.
FAU - Del Mazo-Monsalvo, Isis
AU  - Del Mazo-Monsalvo I
AD  - Instituto Nacional de Cardiologia, Departamento de Bioquimica, Tlalpan D.F. 
      14080, Mexico.
FAU - Saavedra, Emma
AU  - Saavedra E
AD  - Instituto Nacional de Cardiologia, Departamento de Bioquimica, Tlalpan D.F. 
      14080, Mexico.
FAU - Rodriguez-Enriquez, Sara
AU  - Rodriguez-Enriquez S
AD  - Instituto Nacional de Cardiologia, Departamento de Bioquimica, Tlalpan D.F. 
      14080, Mexico.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160816
PL  - Netherlands
TA  - Biochim Biophys Acta Gen Subj
JT  - Biochimica et biophysica acta. General subjects
JID - 101731726
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 14I68GI3OQ (Aminooxyacetic Acid)
RN  - 53-59-8 (NADP)
RN  - 57-04-5 (Dihydroxyacetone Phosphate)
RN  - 9LSH52S3LQ (Dichloroacetic Acid)
RN  - QU60N5OPLG (Oxamic Acid)
SB  - IM
MH  - Aminooxyacetic Acid/*pharmacology
MH  - Animals
MH  - Antineoplastic Agents/pharmacology
MH  - Cell Line, Tumor
MH  - Computer Simulation
MH  - Dichloroacetic Acid/*pharmacology
MH  - Dihydroxyacetone Phosphate/pharmacology
MH  - Energy Metabolism/*drug effects
MH  - Enzyme Inhibitors/pharmacology
MH  - Female
MH  - Glycolysis/drug effects
MH  - Humans
MH  - Kinetics
MH  - Mice
MH  - Mitochondria, Heart/drug effects/metabolism
MH  - Models, Molecular
MH  - NADP/metabolism
MH  - Neoplasms/*metabolism
MH  - Oxamic Acid/*pharmacology
MH  - Oxidative Phosphorylation/drug effects
MH  - Rats, Wistar
MH  - Sus scrofa
OTO - NOTNLM
OT  - Cancer
OT  - Glycolysis
OT  - Kinetic modeling
OT  - Metabolic drugs
OT  - Oxidative phosphorylation
EDAT- 2016/08/20 06:00
MHDA- 2017/11/04 06:00
CRDT- 2016/08/20 06:00
PHST- 2016/03/03 00:00 [received]
PHST- 2016/07/08 00:00 [revised]
PHST- 2016/08/12 00:00 [accepted]
PHST- 2016/08/20 06:00 [pubmed]
PHST- 2017/11/04 06:00 [medline]
PHST- 2016/08/20 06:00 [entrez]
AID - S0304-4165(16)30287-2 [pii]
AID - 10.1016/j.bbagen.2016.08.006 [doi]
PST - ppublish
SO  - Biochim Biophys Acta Gen Subj. 2017 Jan;1861(1 Pt A):3221-3236. doi: 
      10.1016/j.bbagen.2016.08.006. Epub 2016 Aug 16.