Targeting the cancer metabolic phenotype using high dose vitamin B1 therapy

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 exhibits a growth suppressive effect in many cancers. Recently it has been shown that the thiamine co-enzyme, thiamine pyrophosphate, can regulate the phosphorylation of PDH. Therefore, we hypothesize that high dose thiamine can normalize glycolysis in cancer cells leading to a cellular apoptosis. We have determined that high dose vitamin B1 reduces cell proliferation in cancer cell lines by a mechanism involving reduced PDH phosphorylation. Additionally we have established that thiamine homeostasis is up-regulated in cancer and in hypoxic microenvironments. Together these findings suggest that using high dose thiamine may provide an important targeting advantage directed towards altering the cancer metabolic phenotype.