High-dose vitamin B1 reduces proliferation in cancer cell lines analogous to dichloroacetate.
OBJECTIVE
The dichotomous effect of thiamine supplementation on cancer cell growth is characterized by growth stimulation at low doses and growth suppression at high doses. Unfortunately, how thiamine reduces cancer cell proliferation is currently unknown. Recent focuses on metabolic targets for cancer therapy have exploited the altered regulation of the thiamine-dependent enzyme pyruvate dehydrogenase (PDH). Cancer cells inactivate PDH through phosphorylation by overexpression of pyruvate dehydrogenase kinases (PDKs). Inhibition of PDKs by dichloracetate (DCA) exhibits a growth suppressive effect in many cancers. Recently, it has been shown that the thiamine coenzyme, thiamine pyrophosphate reduces PDK-mediated phosphorylation of PDH. Therefore, the objective of this study was to determine whether high-dose thiamine supplementation reduces cell proliferation through a DCA-like mechanism.


METHODS
Cytotoxicity of thiamine and DCA was assessed in SK-N-BE and Panc-1 cancer cell lines. Comparative effects of high-dose thiamine and DCA on PDH phosphorylation were measured by Western blot. The metabolic impact of PDH reactivation was determined by glucose and lactate assays. Changes in the mitochondrial membrane potential, reactive oxygen species (ROS) production, and caspase-3 activation were assessed to characterize the mechanism of action.


RESULTS
Thiamine exhibited a lower IC50 value in both cell lines compared with DCA. Both thiamine and DCA reduced the extent of PDH phosphorylation, reduced glucose consumption, lactate production, and mitochondrial membrane potential. High-dose thiamine and DCA did not increase ROS, but increased caspase-3 activity.


CONCLUSIONS
Our findings suggest that high-dose thiamine reduces cancer cell proliferation by a mechanism similar to that described for dichloroacetate.
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, R.C. Wilson Pharmacy Building, Athens, GA, 30602, USA.
Bradley S
BS
Hanberry
Ryan
R
Berger
Jason A
JA
Zastre
D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000008:administration & dosage*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000096:biosynthesis; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013831:Thiamine / Q000008:administration & dosage*
D011768:Pyruvate Dehydrogenase Complex; D017382:Reactive Oxygen Species; D019344:Lactic Acid; D003999:Dichloroacetic Acid; D053148:Caspase 3; D005947:Glucose; D013831:Thiamine