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High-dose vitamin B1 reduces proliferation in cancer cell lines analogous to dichloroacetate

Cancer Chemotherapy and Pharmacology volume 73, pages 585–594 (2014)Cite this article

Abstract

Purpose

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.

Conclusion

Our findings suggest that high-dose thiamine reduces cancer cell proliferation by a mechanism similar to that described for dichloroacetate.

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References

  1. Hsu PP, Sabatini DM (2008) Cancer cell metabolism: warburg and beyond. Cell 134(5):703–707. doi:10.1016/j.cell.2008.08.021

    Article  CAS  PubMed  Google Scholar 

  2. Gatenby RA, Gillies RJ (2007) Glycolysis in cancer: a potential target for therapy. Int J Biochem Cell Biol 39(7–8):1358–1366. doi:10.1016/j.biocel.2007.03.021

    Article  CAS  PubMed  Google Scholar 

  3. Korotchkina LG, Patel MS (2001) Probing the mechanism of inactivation of human pyruvate dehydrogenase by phosphorylation of three sites. J Biol Chem 276(8):5731–5738. doi:10.1074/jbc.M007558200

    Article  CAS  PubMed  Google Scholar 

  4. Kolobova E, Tuganova A, Boulatnikov I, Popov KM (2001) Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites. Biochem J 358(Pt 1):69–77

    Article  CAS  PubMed  Google Scholar 

  5. Sale GJ, Randle PJ (1981) Analysis of site occupancies in [32P]phosphorylated pyruvate dehydrogenase complexes by aspartyl-prolyl cleavage of tryptic phosphopeptides. Eur J Biochem/FEBS 120(3):535–540

    Article  CAS  Google Scholar 

  6. Yeaman SJ, Hutcheson ET, Roche TE, Pettit FH, Brown JR, Reed LJ, Watson DC, Dixon GH (1978) Sites of phosphorylation on pyruvate dehydrogenase from bovine kidney and heart. Biochemistry 17(12):2364–2370

    Article  CAS  PubMed  Google Scholar 

  7. Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL (2005) Pyruvate dehydrogenase and pyruvate dehydrogenase kinase expression in non small cell lung cancer and tumor-associated stroma. Neoplasia (New York, NY) 7(1):1

    Article  CAS  Google Scholar 

  8. Lin H, Hsieh F, Song H, Lin J (2005) Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer. Br J Cancer 93(12):1372–1381

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. McFate T, Mohyeldin A, Lu H, Thakar J, Henriques J, Halim ND, Wu H, Schell MJ, Tsang TM, Teahan O, Zhou S, Califano JA, Jeoung NH, Harris RA, Verma A (2008) Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem 283(33):22700–22708. doi:10.1074/jbc.M801765200

    Article  CAS  PubMed  Google Scholar 

  10. Lu CW, Lin SC, Chen KF, Lai YY, Tsai SJ (2008) Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem 283(42):28106–28114. doi:10.1074/jbc.M803508200

    Article  CAS  PubMed  Google Scholar 

  11. Wigfield S, Winter S, Giatromanolaki A, Taylor J, Koukourakis M, Harris A (2008) PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer. Br J Cancer 98(12):1975–1984

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Kim JW, Dang CV (2006) Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res 66(18):8927–8930. doi:10.1158/0008-5472.CAN-06-1501

    Article  CAS  PubMed  Google Scholar 

  13. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (2007) A mitochondria-K + channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11(1):37–51. doi:10.1016/j.ccr.2006.10.020

    Article  CAS  PubMed  Google Scholar 

  14. Madhok BM, Yeluri S, Perry SL, Hughes TA, Jayne DG (2010) Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. Br J Cancer 102(12):1746–1752. doi:10.1038/sj.bjc.6605701

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC (2010) Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 120(1):253–260. doi:10.1007/s10549-009-0435-9

    Article  CAS  PubMed  Google Scholar 

  16. Garber K (2006) Energy deregulation: licensing tumors to grow. Science 312(5777):1158–1159. doi:10.1126/science.312 5777.1158

    Article  CAS  PubMed  Google Scholar 

  17. Papandreou I, Goliasova T, Denko NC (2011) Anticancer drugs that target metabolism: is dichloroacetate the new paradigm? Int J Cancer 128(5):1001–1008. doi:10.1002/ijc.25728

    Article  CAS  PubMed  Google Scholar 

  18. Roche TE, Hiromasa Y (2007) Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer. CMLS 64(7–8):830–849. doi:10.1007/s00018-007-6380-z

    Article  CAS  PubMed  Google Scholar 

  19. Comín-Anduix B, Boren J, Martinez S, Moro C, Centelles JJ, Trebukhina R, Petushok N, Lee WNP, Boros LG, Cascante M (2001) The effect of thiamine supplementation on tumour proliferation. Eur J Biochem 268(15):4177–4182

    Article  PubMed  Google Scholar 

  20. Journe F, Laurent G, Chaboteaux C, Nonclercq D, Durbecq V, Larsimont D, Body J-J (2008) Farnesol, a mevalonate pathway intermediate, stimulates MCF-7 breast cancer cell growth through farnesoid-X-receptor-mediated estrogen receptor activation. Breast Cancer Res Treat 107(1):49–61

    Article  CAS  PubMed  Google Scholar 

  21. Langbein S, Zerilli M, Zur Hausen A, Staiger W, Rensch-Boschert K, Lukan N, Popa J, Ternullo MP, Steidler A, Weiss C, Grobholz R, Willeke F, Alken P, Stassi G, Schubert P, Coy JF (2006) Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. Br J Cancer 94(4):578–585. doi:10.1038/sj.bjc.6602962

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Staiger WI, Coy JF, Grobholz R, Hofheinz RD, Lukan N, Post S, Schwarzbach MH, Willeke F (2006) Expression of the mutated transketolase TKTL1, a molecular marker in gastric cancer. Oncol Rep 16(4):657–661

    CAS  PubMed  Google Scholar 

  23. Krockenberger M, Honig A, Rieger L, Coy JF, Sutterlin M, Kapp M, Horn E, Dietl J, Kammerer U (2007) Transketolase-like 1 expression correlates with subtypes of ovarian cancer and the presence of distant metastases. Int J Gynecol Cancer 17(1):101–106. doi:10.1111/j.1525-1438.2007.00799.x

    Article  CAS  PubMed  Google Scholar 

  24. Foldi M, Stickeler E, Bau L, Kretz O, Watermann D, Gitsch G, Kayser G, Zur Hausen A, Coy JF (2007) Transketolase protein TKTL1 overexpression: a potential biomarker and therapeutic target in breast cancer. Oncol Rep 17(4):841–845

    PubMed  Google Scholar 

  25. Stockwin LH, Yu SX, Borgel S, Hancock C, Wolfe TL, Phillips LR, Hollingshead MG, Newton DL (2010) Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC. Int J Cancer 127(11):2510–2519. doi:10.1002/ijc.25499

    Article  CAS  PubMed  Google Scholar 

  26. Knoechel TR, Tucker AD, Robinson CM, Phillips C, Taylor W, Bungay PJ, Kasten SA, Roche TE, Brown DG (2006) Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands. Biochemistry 45(2):402–415. doi:10.1021/bi051402s

    Article  CAS  PubMed  Google Scholar 

  27. Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 99(7):989–994. doi:10.1038/sj.bjc.6604554

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Niewisch MR, Kuci Z, Wolburg H, Sautter M, Krampen L, Deubzer B, Handgretinger R, Bruchelt G (2012) Influence of dichloroacetate (DCA) on lactate production and oxygen consumption in neuroblastoma cells: is DCA a suitable drug for neuroblastoma therapy? Cell Physiol Biochem 29(3–4):373–380. doi:10.1159/000338492

    Article  CAS  PubMed  Google Scholar 

  29. Owen OE, Kalhan SC, Hanson RW (2002) The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem 277(34):30409–30412. doi:10.1074/jbc.R200006200

    Article  CAS  PubMed  Google Scholar 

  30. Grivicich I, Regner A, da Rocha AB, Grass LB, Alves PA, Kayser GB, Schwartsmann G, Henriques JA (2005) Irinotecan/5-fluorouracil combination induces alterations in mitochondrial membrane potential and caspases on colon cancer cell lines. Oncol Res 15(7–8):385–392

    CAS  PubMed  Google Scholar 

  31. Ayyanathan K, Kesaraju S, Dawson-Scully K, Weissbach H (2012) Combination of sulindac and dichloroacetate kills cancer cells via oxidative damage. PLoS ONE 7(7):e39949. doi:10.1371/journal.pone.0039949

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano MC, Shungu DC, Millar WS, Hong X, Gooch CL, Mao X, Pascual JM, Hirano M, Stacpoole PW, DiMauro S, De Vivo DC (2006) Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 66(3):324–330. doi:10.1212/01.wnl.0000196641.05913.27

    Article  CAS  PubMed  Google Scholar 

  33. Singleton CK, Martin PR (2001) Molecular mechanisms of thiamine utilization. Curr Mol Med 1(2):197–207

    Article  CAS  PubMed  Google Scholar 

  34. Smithline HA, Donnino M, Greenblatt DJ (2012) Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects. BMC Clin Pharmacol 12:4. doi:10.1186/1472-6904-12-4

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Meador K, Loring D, Nichols M, Zamrini E, Rivner M, Posas H, Thompson E, Moore E (1993) Preliminary findings of high-dose thiamine in dementia of Alzheimer’s type. J Geriatr Psychiatry Neurol 6(4):222–229

    CAS  PubMed  Google Scholar 

  36. Ganapathy V, Smith SB, Prasad PD (2004) SLC19: the folate/thiamine transporter family. Pflugers Arch 447(5):641–646. doi:10.1007/s00424-003-1068-1

    Article  CAS  PubMed  Google Scholar 

  37. Lindhurst MJ, Fiermonte G, Song S, Struys E, De Leonardis F, Schwartzberg PL, Chen A, Castegna A, Verhoeven N, Mathews CK, Palmieri F, Biesecker LG (2006) Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia. Proc Natl Acad Sci USA 103(43):15927–15932. doi:10.1073/pnas.0607661103

    Article  CAS  PubMed  Google Scholar 

  38. Zastre JA, Hanberry BS, Sweet RL, McGinnis AC, Venuti KR, Bartlett MG, Govindarajan R (2013) Up-regulation of vitamin B1 homeostasis genes in breast cancer. J Nutr Biochem 24(9):1616–1624. doi:10.1016/j.jnutbio.2013.02.002

    Article  CAS  PubMed  Google Scholar 

  39. Lukienko PI, Mel’nichenko NG, Zverinskii IV, Zabrodskaya SV (2000) Antioxidant properties of thiamine. Bull Exp Biol Med 130(9):874–876

    Article  CAS  PubMed  Google Scholar 

  40. Schmid U, Stopper H, Heidland A, Schupp N (2008) Benfotiamine exhibits direct antioxidative capacity and prevents induction of DNA damage in vitro. Diabetes/metab Res Rev 24(5):371–377. doi:10.1002/dmrr.860

    Article  CAS  Google Scholar 

  41. Martin PR, Singleton CK, Hiller-Sturmhofel S (2003) The role of thiamine deficiency in alcoholic brain disease. Alcohol Res Health 27(2):134–142

    PubMed  Google Scholar 

  42. Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8(7):579–591. doi:10.1038/nrd2803

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

These studies were supported by the Georgia Cancer Coalition through the Distinguished Cancer Scholar Program awarded to Jason Zastre. The authors would like to thank Dr. James Franklin for his assistance with mitochondrial membrane potential assays.

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  1. Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, R.C. Wilson Pharmacy Building, Athens, GA, 30602, USA

    Bradley S. Hanberry, Ryan Berger & Jason A. Zastre

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  1. Bradley S. Hanberry
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  2. Ryan Berger
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Correspondence to Jason A. Zastre.

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Hanberry, B.S., Berger, R. & Zastre, J.A. High-dose vitamin B1 reduces proliferation in cancer cell lines analogous to dichloroacetate. Cancer Chemother Pharmacol 73, 585–594 (2014). https://doi.org/10.1007/s00280-014-2386-z

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  • DOI: https://doi.org/10.1007/s00280-014-2386-z

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