The effect of thiamine supplementation on tumour proliferation

Abstract

Thiamine deficiency frequently occurs in patients with advanced cancer and therefore thiamine supplementation is used as nutritional support. Thiamine (vitamin B1) is metabolized to thiamine pyrophosphate, the cofactor of transketolase, which is involved in ribose synthesis, necessary for cell replication. Thus, it is important to determine whether the benefits of thiamine supplementation outweigh the risks of tumor proliferation. Using oxythiamine (an irreversible inhibitor of transketolase) and metabolic control analysis (MCA) methods, we measured an in vivo tumour growth control coefficient of 0.9 for the thiamine-transketolase complex in mice with Ehrlich's ascites tumour. Thus, transketolase enzyme and thiamine clearly determine cell proliferation in the Ehrlich's ascites tumour model. This high control coefficient allows us to predict that in advanced tumours, which are commonly thiamine deficient, supplementation of thiamine could significantly increase tumour growth through transketolase activation. The effect of thiamine supplementation on tumour proliferation was demonstrated by in vivo experiments in mice with the ascites tumour. Thiamine supplementation in doses between 12.5 and 250 times the recommended dietary allowance (RDA) for mice were administered starting on day four of tumour inoculation. We observed a high stimulatory effect on tumour growth of 164% compared to controls at a thiamine dose of 25 times the RDA. This growth stimulatory effect was predicted on the basis of correction of the pre-existing level of thiamine deficiency (42%), as assayed by the cofactor/ enzyme ratio. Interestingly, at very high overdoses of thiamine, < 2500 times the RDA, thiamine supplementation had the opposite effect and caused 10% inhibition of tumour growth. This effect was heightened, resulting in a 36% decrease, when thiamine supplementation was administered from the 7th day prior to tumour inoculation. Our results show that thiamine supplementation sufficient to correct existing thiamine deficiency stimulates tumour proliferation as predicted by MCA. The tumour inhibitory effect at high doses of thiamine is unexplained and merits further study.Keywords: transketolase; thiamine; Ehrlich's ascites tumour; metabolic control analysis.One of the most disturbing facts about cancer is that prevalence rates are still rising despite the resources that have been developed over the last three decades for understanding and controlling it more efficiently [1]. Cancer is currently seen as a complex genetic phenomenon characterized by breakdown in the integrity or function of cellular growth-regulating genes and their signalling pathways [2,3]. The increasing worldwide cancer epidemic raises the need for novel approaches to treating it, not only as a genetic abnormality but also as a metabolic disease. As tumour cells are metabolically unbalanced with respect to surrounding tissue, an alternative approach to new cancer drug development is the analysis of metabolic reaction network in tumour cells and determining the contr...

Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted

“…Transketolase enzyme reactions control the nonoxidative part of the PPP. Using metabolic control analysis methods and oxythiamine, Comin-Anduix et al (2001) demonstrated that transketolase enzyme reactions determine cell proliferation in the Ehrlich's ascites tumour model. The transketolase enzyme reactions and other reactions of the PPP allow glucose conversion to ribose for nucleic acid synthesis and generate NADPH, a reducing agent required for synthesis reactions.…”

“…The most effective way to inhibit tumour proliferation should be to block the generation of energy for tumour growth. Metabolic control analysis and inhibition of transketolase enzyme reactions have already shown that tumour proliferation can be inhibited by anti-transketolase approaches (Rais et al, 1999;Boros et al, 2001a, b;Comin-Anduix et al, 2001Du et al, 2004). These successful results have been attributed to TKT transketolase.…”

“…The importance of transketolases for tumour cell metabolism is underlined by the fact that the application of specific transketolase inhibitors to tumours induces a dramatic reduction in tumour cell proliferation (Rais et al, 1999). In addition, the activation of transketolases by application of thiamine stimulates tumour growth (Comin-Anduix et al, 2001). Furthermore, several natural products have been reported to inhibit transketolase enzyme activity in vitro, and also to inhibit cell proliferation or suppress tumour growth in mouse models or cancer patients as a result of reduction of transketolase activity (Hidvegi et al, 1999;Boros et al, 2001a, b;Comin-Anduix et al, 2002;Jakab et al, 2003).…”

Hypoxia induced upregulation and function of the thiamine transporter, SLC19A3 in a breast cancer cell line

“…Clinically, thiamine deficiencies have been reported in advanced cancer patients and high dose thiamine supplementation is commonly used as a nutritional supplement. [51][52][53] However, increasing thiamine supplementation 12-25 times the recommended daily allowance to mice stimulated the growth of an Ehrlich's ascites tumor model. 51 Therefore, the increase in SLC19A3 expression and the corresponding enhancement in thiamine transport under hypoxia may be a critical pro-survival response to supply thiamine in support of the PPP and maintenance of tumor cell metabolism and proliferation within hypoxic microenvironments.…”

Type B Lactic Acidosis Secondary to Thiamine Deficiency in a Child With Malignancy

“…9 Certain tumor cells overexpress glycolytic enzymes such as hexokinase, which may also help facilitate rapid proliferation. 10 The neoplastic tissue beds in solid tumors are relatively ischemic compared with normal tissue, 11 and these cells often use anaerobic metabolism, which leads to lactate accumulation.…”