Thiamine mimetics sulbutiamine and benfotiamine as a nutraceutical approach to anticancer therapy

Jonus, Hunter C.; Byrnes, Charnel C.; Kim, Jaeah; Valle, María Luisa del; Bartlett, Michael G.; Said, Hamid M.; Zastre, Jason

doi:10.1016/j.biopha.2019.109648

Cited by 15 publications

(13 citation statements)

References 46 publications

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“…In malignant tumor cells, pyruvate-dehydrogenase-kinase-mediated glycolysis is enhanced to maintain their rapid growth. Highdose thiamine can reduce pyruvate dehydrogenase kinase activity and therefore plays an anti-tumor role in xenograft mice (Jonus et al, 2020). In this study, the significant decreased of thiamine metabolism in DLBCL patients suggests that this disturbance of thiamine metabolism of the gut microbiota may cause abnormal glucose metabolism, leading to the occurrence and development of DLBCL although further studies on the detailed mechanism are needed.…”

Section: Discussionmentioning

confidence: 71%

Gut Microbiota in Untreated Diffuse Large B Cell Lymphoma Patients

Wang

Zhang

et al. 2021

Front. Microbiol.

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Intestinal microecology plays an important role in the development and progression of hematological malignancies. However, characteristics of gut microbiota in diffuse large B cell lymphoma (DLBCL) have not been reported. The microbiota composition of fecal samples from 25 untreated DLBCL patients and 26 healthy volunteers was examined by 16S rRNA gene sequencing. On α-diversity analysis, there was no significant difference in species diversity and abundance between the two groups. However, a significant difference was observed on β-diversity analysis. The intestinal microbiota in patients with DLBCL showed a continuous evolutionary relationship, which progressed from phylum, proteobacteria, to genus, Escherichia-Shigella. Their abundance was significantly higher than that of the control group. At the genus level, Allisonella, lachnospira, and Roseburia were more abundant in patients with DLBCL than in the control group. Functional prediction by PICRUSt indicated that thiamine metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis were significantly lower in the DLBCL group than in the control group. In conclusion, our results clearly demonstrate that the gut microbiota was changed significantly in DLBCL. The study highlights fundamental differences in the microbial diversity and composition of patients with DLBCL and paves the way for future prospective studies and microbiome-directed interventional trials to improve patient outcomes.

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Section: Discussionmentioning

confidence: 71%

Gut Microbiota in Untreated Diffuse Large B Cell Lymphoma Patients

Wang

Zhang

et al. 2021

Front. Microbiol.

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“…Thiamine is a precursor of the PDH coenzyme, thiamine diphosphate (ThDP), that is the major component of thiamine pool in most tissues [ 20 ]. In addition to this coenzyme role, thiamine and its derivatives regulate multiple protein targets by non-coenzyme binding which is observed not only among the enzymes metabolically linked to PDHC [ 13 , 21 , 22 ], but also among general regulators of oxidative metabolism, such as transcriptional factor p53 and PDH kinases [ 21 , 23 , 24 , 25 , 26 , 27 ]. In particular, ThDP may activate PDHC function directly (as a coenzyme), and indirectly (as an inhibitor of PDH kinases).…”

Section: Introductionmentioning

confidence: 99%

“…In particular, ThDP may activate PDHC function directly (as a coenzyme), and indirectly (as an inhibitor of PDH kinases). The ThDP interaction with p53 and PDH kinases is important for the anticancer action of thiamine and its derivatives [ 23 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Daytime Dependence of the Activity of the Rat Brain Pyruvate Dehydrogenase Corresponds to the Mitochondrial Sirtuin 3 Level and Acetylation of Brain Proteins, All Regulated by Thiamine Administration Decreasing Phosphorylation of PDHA Ser293

Aleshin

Artiukhov

Kaehne

et al. 2021

IJMS

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Coupling glycolysis and mitochondrial tricarboxylic acid cycle, pyruvate dehydrogenase (PDH) complex (PDHC) is highly responsive to cellular demands through multiple mechanisms, including PDH phosphorylation. PDHC also produces acetyl-CoA for protein acetylation involved in circadian regulation of metabolism. Thiamine (vitamin B1) diphosphate (ThDP) is known to activate PDH as both coenzyme and inhibitor of the PDH inactivating kinases. Molecular mechanisms integrating the function of thiamine-dependent PDHC into general redox metabolism, underlie physiological fitness of a cell or an organism. Here, we characterize the daytime- and thiamine-dependent changes in the rat brain PDHC function, expression and phosphorylation, assessing their impact on protein acetylation and metabolic regulation. Morning administration of thiamine significantly downregulates both the PDH phosphorylation at Ser293 and SIRT3 protein level, the effects not observed upon the evening administration. This action of thiamine nullifies the daytime-dependent changes in the brain PDHC activity and mitochondrial acetylation, inducing diurnal difference in the cytosolic acetylation and acetylation of total brain proteins. Screening the daytime dependence of central metabolic enzymes and proteins of thiol/disulfide metabolism reveals that thiamine also cancels daily changes in the malate dehydrogenase activity, opposite to those of the PDHC activity. Correlation analysis indicates that thiamine abrogates the strong positive correlation between the total acetylation of the brain proteins and PDHC function. Simultaneously, thiamine heightens interplay between the expression of PDHC components and total acetylation or SIRT2 protein level. These thiamine effects on the brain acetylation system change metabolic impact of acetylation. The changes are exemplified by the thiamine enhancement of the SIRT2 correlations with metabolic enzymes and proteins of thiol-disulfide metabolism. Thus, we show the daytime- and thiamine-dependent changes in the function and phosphorylation of brain PDHC, contributing to regulation of the brain acetylation system and redox metabolism. The daytime-dependent action of thiamine on PDHC and SIRT3 may be of therapeutic significance in correcting perturbed diurnal regulation.

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“…Therefore, the results from our study showed that the abundance of Lactobacillus fermentum was signi cantly higher in CRG than that of the NCRG, suggesting that Lactobacillus fermentum may inhibit DLBCL [29] PICRUSt was used to predict the microbial function based on the 16S rRNA gene sequencing data, which showed that the Thiamine metabolism function of gut microbiota in PRG and POG was signi cantly lower than that of CG. High dose Thiamine can reduce pyruvate dehydrogenase kinase activity and play anti-tumor role in xenograft mice [33] . Therefore, it is speculated that the gut microbiota causes the DLBCL micro-environment to remain in the state of low thiamine, which leads to the over-expression of pyruvate dehydrogenase kinase, increasing the glycolytic process of cancer cells leading to tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Correlation of Gut Microbiota with Efficacy of Chemotherapy in Patients with Diffuse Large B-cell Lymphoma

Zhang

et al. 2021

Preprint

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The composition and diversity of gut microbiota (GMB) have been reported to be associated with the occurrence and progression as well as treatment outcome in many diseases. Our previous study demonstrated that the GMB was changed significantly and Proteobacteria phylum was the dominant microbiota in untreated diffuse large B-cell lymphoma (DLBCL) patients compared with healthy controls. This study aims to investigate the association of GMB with treatment outcomes in patients with DLBCL. 17 Patients with DLBCL and 18 healthy volunteers were recruited at Peking Union Medical College Hospital. The GMB of fecal samples was analyzed using 16S ribosomal RNA gene sequencing. We examined GMB compositions in 3 contexts: DLBCL patients (17) compared with healthy controls (18), DLBCL patients pretreatment (17) compared with posttreatment (17), and the association of GMB with chemotherapy treatment outcomes (10 complete remissions, 7 non-complete remisisons). We found that the GMB was changed considerably in posttreatment DLBCL patients. More specifically, the abundance of Proteobacteria phylum decreased significantly in patients following 4 courses of chemotherapy, although no significant difference from healthy comtrols(CG). In addition, the abundance of Lactobacillaceae, Lactobacillus, Lactobacillus fermentum were significantly higher and became dominant gut microbiota in DLBCL patients with complete remission, ,which may be associated with chemotherapy intervention and tumor extinction. Lactobacillus fermentum may have an inhibitory effect on DLBCL contributing to the disease remisison. The composition of gut microbiota in DLBCL patients changed from the healthy condition to the pretreatment condition, and then turned to the posttreatment condition after chemotherapy, which echoed the pathological succession of gut microbiota in DLBCL patients. Results from our current study together with previous research will provide a rational foundation for further investigation on the pathogenesis of gut microbiota in DLBCL to facilitate drug development and foster novel strategy for the better management of patients with DLBCL.

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Thiamine mimetics sulbutiamine and benfotiamine as a nutraceutical approach to anticancer therapy

Cited by 15 publications

References 46 publications

Gut Microbiota in Untreated Diffuse Large B Cell Lymphoma Patients

Gut Microbiota in Untreated Diffuse Large B Cell Lymphoma Patients

Daytime Dependence of the Activity of the Rat Brain Pyruvate Dehydrogenase Corresponds to the Mitochondrial Sirtuin 3 Level and Acetylation of Brain Proteins, All Regulated by Thiamine Administration Decreasing Phosphorylation of PDHA Ser293

Correlation of Gut Microbiota with Efficacy of Chemotherapy in Patients with Diffuse Large B-cell Lymphoma

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