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A reduced curcuminoid analog as a novel inducer of fetal hemoglobin

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Abstract

Thalassemia is an inherited disorder of hemoglobin molecules that is characterized by an imbalance of α- and β-globin chain synthesis. Accumulation of unbound α-globin chains in erythroid cells is the major cause of pathology in β-thalassemia. Stimulation of γ-globin production can ameliorate disease severity as it combines with the α-globin to form fetal hemoglobin. We examined γ-globin-inducing effect of curcuminoids extracted from Curcuma longa L. and their metabolite reduced forms in erythroid leukemia K562 and human primary erythroid precursor cells. The results showed that curcuminoid compounds, especially bisdemethoxycurcumin are potential γ-globin enhancers. We also demonstrated that its reduced analog, hexahydrobisdemethoxycurcumin (HHBDMC), is most effective and leads to induction of γ-globin mRNA and HbF in primary erythroid precursor cells for 3.6 ± 0.4- and 2.0 ± 0.4-folds, respectively. This suggested that HHBDMC is the potential agent to be developed as a new therapeutic drug for β-thalassemia and related β-hemoglobinopathies.

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Abbreviations

Hb:

Hemoglobin

BDMC:

Bisdemethoxycurcumin

THBDMC:

Tetrahydrobisdemethoxycurcumin

HHBDMC:

Hexahydrobisdemethoxycurcumin

OHBDMC:

Octahydrobisdemethoxycurcumin

References

  1. Cao A, Galanello R (2010) β-thalassemia. Genet Med 12(2):61–76

    Article  PubMed  CAS  Google Scholar 

  2. Rund D, Rachmilewitz E (2005) β-thalassemia. N Engl J Med 353(11):1135–1146

    Article  PubMed  CAS  Google Scholar 

  3. Thein SL (2008) Genetic modifiers of the β-haemoglobinopathies. Br J Haematol 141(3):357–366

    Article  PubMed  CAS  Google Scholar 

  4. Perrine SP, Castaneda SA, Chui DH, Faller DV, Berenson RJ, Siritanaratku N, Fucharoen S (2010) Fetal globin gene inducers: novel agents and new potential. Ann N Y Acad Sci 1202:158–164

    Article  PubMed  CAS  Google Scholar 

  5. El-Beshlawy A, Hamdy M, El Ghamrawy M (2009) Fetal globin induction in β-thalassemia. Hemoglobin 33(Suppl 1):S197–S203

    Article  PubMed  CAS  Google Scholar 

  6. Testa U (2009) Fetal hemoglobin chemical inducers for treatment of hemoglobinopathies. Ann Hematol 88(6):505–528

    Article  PubMed  CAS  Google Scholar 

  7. Bianchi N, Zuccato C, Lampronti I, Borgatti M, Gambari R (2009) Fetal hemoglobin inducers from the natural world: a novel approach for identification of drugs for the treatment of β-thalassemia and sickle-cell anemia. Evid Based Complement Alternat Med 6(2):141–151

    Article  PubMed  Google Scholar 

  8. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV (2008) Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci 65(11):1631–1652

    Article  PubMed  CAS  Google Scholar 

  9. Sharma RA, Gescher AJ, Steward WP (2005) Curcumin: the story so far. Eur J Cancer 41(13):1955–1968

    Article  PubMed  CAS  Google Scholar 

  10. Changtam C, de Koning HP, Ibrahim H, Sajid MS, Gould MK, Suksamrarn A (2010) Curcuminoid analogs with potent activity against Trypanosoma and Leishmania species. Eur J Med Chem 45(3):941–956

    Article  PubMed  CAS  Google Scholar 

  11. Changtam C, Hongmanee P, Suksamrarn A (2010) Isoxazole analogs of curcuminoids with highly potent multidrug-resistant antimycobacterial activity. Eur J Med Chem 45(10):4446–4457

    Article  PubMed  CAS  Google Scholar 

  12. Portes E, Gardrat C, Castellan A (2007) A comparative study on the antioxidant properties of tetrahydrocurcuminoids and curcuminoids. Tetrahedron 63:9092–9099

    Article  CAS  Google Scholar 

  13. Vadolas J, Wardan H, Orford M, Williamson R, Ioannou PA (2004) Cellular genomic reporter assays for screening and evaluation of inducers of fetal hemoglobin. Hum Mol Genet 13(2):223–233

    Article  PubMed  CAS  Google Scholar 

  14. Perrine SP, Mankidy R, Boosalis MS, Bieker JJ, Faller DV (2009) Erythroid Kruppel-like factor (EKLF) is recruited to the γ-globin gene promoter as a co-activator and is required for γ-globin gene induction by short-chain fatty acid derivatives. Eur J Haematol 82(6):466–476

    Article  PubMed  CAS  Google Scholar 

  15. Tubsuwan A, Munkongdee T, Jearawiriyapaisarn N, Boonchoy C, Winichagoon P, Fucharoen S, Svasti S (2011) Molecular analysis of globin gene expression in different thalassaemia disorders: individual variation of βE pre-mRNA splicing determine disease severity. Br J Haematol 154(5):635–643

    Article  PubMed  CAS  Google Scholar 

  16. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007) Bioavailability of curcumin: problems and promises. Mol Pharm 4(6):807–818

    Article  PubMed  CAS  Google Scholar 

  17. Lao CD, Ruffin MT, Normolle D, Heath DD, Murray SI, Bailey JM, Boggs ME, Crowell J, Rock CL, Brenner DE (2006) Dose escalation of a curcuminoid formulation. BMC Complement Altern Med 6:10

    Article  PubMed  Google Scholar 

  18. Sharma RA, McLelland HR, Hill KA, Ireson CR, Euden SA, Manson MM, Pirmohamed M, Marnett LJ, Gescher AJ, Steward WP (2001) Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res 7(7):1894–1900

    PubMed  CAS  Google Scholar 

  19. Tocharus J, Jamsuwan S, Tocharus C, Changtam C, Suksamrarn A (2012) Curcuminoid analogs inhibit nitric oxide production from LPS-activated microglial cells. J Nat Med 66(2):400–405

    Article  PubMed  CAS  Google Scholar 

  20. Fibach E, Prus E, Bianchi N, Zuccato C, Breveglieri G, Salvatori F, Finotti A, Lipucci di Paola M, Brognara E, Lampronti I, Borgatti M, Gambari R (2012) Resveratrol: Antioxidant activity and induction of fetal hemoglobin in erythroid cells from normal donors and β-thalassemia patients. Int J Mol Med 29(6):974–982

    PubMed  CAS  Google Scholar 

  21. Lampronti I, Bianchi N, Borgatti M, Fibach E, Prus E, Gambari R (2003) Accumulation of γ-globin mRNA in human erythroid cells treated with angelicin. Eur J Haematol 71(3):189–195

    Article  PubMed  CAS  Google Scholar 

  22. Chokchaisiri R, Chaneiam N, Svasti S, Fucharoen S, Vadolas J, Suksamrarn A (2010) Labdane diterpenes from the aerial parts of Curcuma comosa enhance fetal hemoglobin production in an erythroid cell line. J Nat Prod 73(4):724–728

    Article  PubMed  CAS  Google Scholar 

  23. Guerrini A, Lampronti I, Bianchi N, Zuccato C, Breveglieri G, Salvatori F, Mancini I, Rossi D, Potenza R, Chiavilli F, Sacchetti G, Gambari R, Borgatti M (2009) Bergamot (Citrus bergamia Risso) fruit extracts as γ-globin gene expression inducers: phytochemical and functional perspectives. J Agric Food Chem 57(10):4103–4111

    Article  PubMed  CAS  Google Scholar 

  24. Fu S, Kurzrock R (2010) Development of curcumin as an epigenetic agent. Cancer 116(20):4670–4676

    Article  PubMed  CAS  Google Scholar 

  25. Huang J, Plass C, Gerhauser C (2011) Cancer chemoprevention by targeting the epigenome. Curr Drug Targets 12(13):1924–1956

    Article  Google Scholar 

  26. Jha AK, Nikbakht M, Parashar G, Shrivastava A, Capalash N, Kaur J (2010) Reversal of hypermethylation and reactivation of the RARβ2 gene by natural compounds in cervical cancer cell lines. Folia Biol (Praha) 56(5):195–200

    CAS  Google Scholar 

  27. Liu Z, Xie Z, Jones W, Pavlovicz RE, Liu S, Yu J, Li PK, Lin J, Fuchs JR, Marcucci G, Li C, Chan KK (2009) Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett 19(3):706–709

    Article  PubMed  Google Scholar 

  28. Meeran SM, Ahmed A, Tollefsbol TO (2010) Epigenetic targets of bioactive dietary components for cancer prevention and therapy. Clin Epigenetics 1(3–4):101–116

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported in part by Office of the Higher Education Commission and Mahidol University under the National Research University Initiative, The Thailand Research Fund (TRF) and National Science and Technology Development Agency, Thailand. NC was supported by the Strategic Scholarship Fellowship Frontier Research Networks, Office of the Higher Education Commission and Mahidol University. C.C. and A.S. acknowledge supports from the Strategic Basic Research Grant of TRF and the Center of Excellence for Innovation in Chemistry, Office of the Higher Education Commission.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Institute of Nutrition, Mahidol University, Nakhonpathom, 73170, Thailand

    Nattawara Chaneiam

  2. Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhonpathom, 73170, Thailand

    Nattawara Chaneiam, Thongperm Mungkongdee, Pranee Winichagoon, Suthat Fucharoen & Saovaros Svasti

  3. Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, 10240, Thailand

    Chatchawan Changtam & Apichart Suksamrarn

  4. Department of Pediatric, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand

    Umaporn Suthatvoravut

  5. CAGT Research Group, The Murdoch Childrens Research Institute, Royal Children’s Hospital, Melbourne, VIC, 3052, Australia

    Jim Vadolas

  6. Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand

    Saovaros Svasti

Authors
  1. Nattawara Chaneiam
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  2. Chatchawan Changtam
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  3. Thongperm Mungkongdee
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  4. Umaporn Suthatvoravut
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  6. Jim Vadolas
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  8. Suthat Fucharoen
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  9. Saovaros Svasti
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Correspondence to Saovaros Svasti.

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Chaneiam, N., Changtam, C., Mungkongdee, T. et al. A reduced curcuminoid analog as a novel inducer of fetal hemoglobin. Ann Hematol 92, 379–386 (2013). https://doi.org/10.1007/s00277-012-1604-1

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  • DOI: https://doi.org/10.1007/s00277-012-1604-1

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