Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells.
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.
Madhok
B M
BM
Section of Translational Anaesthesia & Surgery, University of Leeds, Level 7 Clinical Sciences Building, St. James's University Hospital, Leeds, UK. umbm@leeds.ac.uk
Yeluri
S
S
Perry
S L
SL
Hughes
T A
TA
Jayne
D G
DG
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
D004791:Enzyme Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019344:Lactic Acid; D003999:Dichloroacetic Acid; D017346:Protein Serine-Threonine Kinases; D010100:Oxygen