PMID- 20485289
OWN - NLM
STAT- MEDLINE
DCOM- 20100701
LR  - 20240404
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 102
IP  - 12
DP  - 2010 Jun 8
TI  - Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer 
      cells.
PG  - 1746-52
LID - 10.1038/sj.bjc.6605701 [doi]
AB  - BACKGROUND: Cancer cells are highly dependent on glycolysis. Our aim was to 
      determine if switching metabolism from glycolysis towards mitochondrial 
      respiration would reduce growth preferentially in colorectal cancer cells over 
      normal cells, and to examine the underlying mechanisms. METHODS: Representative 
      colorectal cancer and non-cancerous cell lines were treated with dichloroacetate 
      (DCA), an inhibitor of pyruvate dehydrogenase kinase. RESULTS: Dichloroacetate 
      (20 mM) did not reduce growth of non-cancerous cells but caused significant 
      decrease in cancer cell proliferation (P=0.009), which was associated with 
      apoptosis and G(2) phase cell-cycle arrest. The largest apoptotic effect was 
      evident in metastatic LoVo cells, in which DCA induced up to a ten-fold increase 
      in apoptotic cell counts after 48 h. The most striking G(2) arrest was evident in 
      well-differentiated HT29 cells, in which DCA caused an eight-fold increase in 
      cells in G(2) phase after 48 h. Dichloroacetate reduced lactate levels in growth 
      media and induced dephosphorylation of E1alpha subunit of pyruvate dehydrogenase 
      complex in all cell lines, but the intrinsic mitochondrial membrane potential was 
      reduced in only cancer cells (P=0.04). CONCLUSIONS: Pyruvate dehydrogenase kinase 
      inhibition attenuates glycolysis and facilitates mitochondrial oxidative 
      phosphorylation, leading to reduced growth of colorectal cancer cells but not of 
      non-cancerous cells.
FAU - Madhok, B M
AU  - Madhok BM
AD  - Section of Translational Anaesthesia & Surgery, University of Leeds, Level 7 
      Clinical Sciences Building, St. James's University Hospital, Leeds, UK. 
      umbm@leeds.ac.uk
FAU - Yeluri, S
AU  - Yeluri S
FAU - Perry, S L
AU  - Perry SL
FAU - Hughes, T A
AU  - Hughes TA
FAU - Jayne, D G
AU  - Jayne DG
LA  - eng
PT  - Journal Article
DEP - 20100518
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase)
RN  - 33X04XA5AT (Lactic Acid)
RN  - 9LSH52S3LQ (Dichloroacetic Acid)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Colorectal Neoplasms/*pathology
MH  - Dichloroacetic Acid/*pharmacology
MH  - Enzyme Inhibitors/*pharmacology
MH  - G2 Phase/drug effects
MH  - Humans
MH  - Lactic Acid/metabolism
MH  - Oxygen/metabolism
MH  - Protein Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Pyruvate Dehydrogenase Acetyl-Transferring Kinase
PMC - PMC2883702
EDAT- 2010/05/21 06:00
MHDA- 2010/07/02 06:00
PMCR- 2011/06/08
CRDT- 2010/05/21 06:00
PHST- 2010/05/21 06:00 [entrez]
PHST- 2010/05/21 06:00 [pubmed]
PHST- 2010/07/02 06:00 [medline]
PHST- 2011/06/08 00:00 [pmc-release]
AID - 6605701 [pii]
AID - 10.1038/sj.bjc.6605701 [doi]
PST - ppublish
SO  - Br J Cancer. 2010 Jun 8;102(12):1746-52. doi: 10.1038/sj.bjc.6605701. Epub 2010 
      May 18.