Skip to main content

Advertisement

SpringerLink
Log in

Increase in γ-globin mRNA content in human erythroid cells treated with angelicin analogs

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

The aim of the present study was to identify molecular analogs of angelicin (ANG) able to increase erythroid differentiation of K562 cells and expression of γ-globin genes in human erythroid precursor cells, with low effects on apoptosis. ANG-like molecules are well-known photosensitizers largely used for their antiproliferative activity in the treatment of different skin diseases (i.e., psoriasis, vitiligo, eczema, and mycosis fungoides). To verify the activity of these derivatives, we employed three experimental cell systems: (1) the human leukemic K562 cell line, (2) K562 cell clones stably transfected with a pCCL construct carrying green-EGFP under the γ-globin gene promoter, and (3) the two-phase liquid culture of human erythroid progenitors isolated from normal donors and β-thalassemia patients. The results of our study suggest that trimethyl ANG is a powerful inducer of erythroid differentiation, compared with known inducers, such as ANG, cytosine arabinoside, mithramycin, and cisplatin. These data could have practical relevance, because pharmacologically mediated regulation of human γ-globin gene expression, with the consequent induction of fetal hemoglobin, is considered a potential therapeutic approach in hematological disorders including β-thalassemia and sickle cell anemia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Rodgers GP, Rachmilewitz EA. Novel treatment options in the severe β-globin disorder. Br J Haematol. 1995;91:263–8.

    Article  CAS  PubMed  Google Scholar 

  2. Rochette J, Craig JE, Thein SL. Fetal hemoglobin levels in adults. Blood Rev. 1994;8:213–24.

    Article  CAS  PubMed  Google Scholar 

  3. Olivieri NF, Rees DC, Ginder DG, Thein SL, Waye JS, Chang L, et al. Elimination of transfusion through induction of fetal hemoglobin synthesis in Cooley’s anemia. Ann NY Acad Sci USA. 1998;850:100–9.

    Article  CAS  Google Scholar 

  4. Swank RA, Stamatoyannopoulos G. Fetal gene reactivation. Curr Opin Genet Dev. 1998;8:366–70.

    Article  CAS  PubMed  Google Scholar 

  5. Steinberg MH, Lu ZH, Barton FB, Terrin ML, Charache S, Dover GJ. Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea: multicenter study of hydroxyurea. Blood. 1997;89:1078–88.

    CAS  PubMed  Google Scholar 

  6. Fibach E, Prasanna P, Rodgers GP, Samid D. Enhanced fetal hemoglobin production by phenylacetate and 4-phenylbutyrate in erythroid precursors derived from normal donors and patients with sickle cell anemia and β-thalassemia. Blood. 1993;82:2203–9.

    CAS  PubMed  Google Scholar 

  7. Rodgers GP, Dover GJ, Uyesaka N, Noguchi CT, Schechter AN, Nienhuis AW. Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cells disease. N Engl J Med. 1993;328:73–80.

    Article  CAS  PubMed  Google Scholar 

  8. Perrine SP, Ginder GD, Faller DV, Dover GH, Ikuta T, Witkowska HE, et al. A short-term trial of butyrate to stimulate fetal-globin gene expression in the β-globin disorders. N Engl J Med. 1993;328:81–6.

    Article  CAS  PubMed  Google Scholar 

  9. Bianchi N, Osti F, Rutigliano C, Ginanni Corradini F, Borsetti E, Tomassetti M, et al. The DNA-binding drugs mithramycin and chromomycin are powerful inducers of erythroid differentiation of human K562 cells. Br J Haematol. 1999;104:258–63.

    Article  CAS  PubMed  Google Scholar 

  10. Bianchi N, Ongaro F, Chiarabelli C, Gualandi L, Mischiati C, Bergamini P, et al. Induction of erythroid differentiation of human K562 cells by cisplatin analogs. Biochem Pharmacol. 2000;60:31–40.

    Article  CAS  PubMed  Google Scholar 

  11. Bianchi N, Chiarabelli C, Borgatti M, Mischiati C, Fibach E, Gambari R. Accumulation of gamma-globin mRNA and induction of erythroid differentiation after treatment of human leukemia K562 cells with tallimustine. Br J Haematol. 2001;113:951–61.

    Article  CAS  PubMed  Google Scholar 

  12. Lampronti I, Bianchi N, Borgatti M, Fibach E, Prus E, Gambari R. Accumulation of gamma-globin mRNA in human erythroid cells treated with angelicin. Eur J Haematol. 2003;71:189–95.

    Article  CAS  PubMed  Google Scholar 

  13. Chilin A, Marzano C, Guiotto A, Manzini P, Baccichetti F, Carlassare F, et al. Synthesis and biological activity of (hydroxymethyl)- and (diethylaminomethyl)-benzopsoralens. J Med Chem. 1999;42:2936–45.

    Article  CAS  PubMed  Google Scholar 

  14. Bordin F, Marzano C, Baccichetti F, Carlassare F, Vedaldi D, Falcomer S, et al. Photobiological properties of 1′-thieno-4, 6, 4′-trimethylangelicin. Photochem Photobiol. 1998;68:157–63.

    CAS  PubMed  Google Scholar 

  15. Conconi MT, Montesi F, Parnigotto PP. Antiproliferative activity and phototoxicity of some methyl derivatives of 5-methoxypsoralen and 5-methoxyangelicin. Pharmacol Toxicol. 1998;82:193–8.

    Article  CAS  PubMed  Google Scholar 

  16. Marzano C, Caffieri S, Fossa P, Bordin F. Activity of 3-carbethoxyangelicin photolysis products. J Photochem Photobiol B. 1997;38:189–95.

    Article  CAS  PubMed  Google Scholar 

  17. Bordin F, Dall’Acqua F, Guiotto A. Angelicins, angular analogs of psoralens: chemistry, photochemical, photobiological and phototherapeutic properties. Pharmacol Ther. 1991;52:331–63.

    Article  CAS  PubMed  Google Scholar 

  18. Guiotto A, Rodighiero P, Manzini P, Pastorini G, Bordin F, Baccichetti F, et al. 6-Methylangelicins: a new series of potential photochemotherapeutic agents for the treatment of psoriasis. J Med Chem. 1984;27:959–67.

    Article  CAS  PubMed  Google Scholar 

  19. Komura J, Ikehata H, Hosoi Y, Riggs AD, Ono T. Mapping psoralen cross-links at the nucleotide level in mammalian cells: suppression of cross-linking at transcription factor- or nucleosome-binding sites. Biochemistry. 2001;40:4096–105.

    Article  CAS  PubMed  Google Scholar 

  20. Mosti L, Lo Presti E, Menozzi G, Marzano C, Baccichetti F, Falcone G, et al. Synthesis of angelicin heteroanalogues: preliminary photobiological and pharmacological studies. Farmaco. 1998;53:602–10.

    Article  CAS  PubMed  Google Scholar 

  21. Lozzio BB, Lozzio CB. Properties of the K562 cell line derived from a patient with chronic myeloid leukemia. Int J Cancer. 1977;19(1):136.

    Article  CAS  PubMed  Google Scholar 

  22. Gambari R, Del Senno L, Barbieri R, Viola L, Tripodi M, Raschella G, et al. Human leukemia K-562 cells: induction of erythroid differentiation by 5-azacytidine. Cell Differ. 1984;14:87–97.

    Article  CAS  PubMed  Google Scholar 

  23. Fibach E, Manor D, Oppenheim A, Rachmilewitz EA. Proliferation and maturation of human erythroid progenitors in liquid medium. Blood. 1989;73:100–3.

    CAS  PubMed  Google Scholar 

  24. Pope SH, Fibach E, Sun J, Chin K, Rodgers GP. Two phase liquid culture system models normal human adult erythropoiesis at the molecular level. Eur J Haematol. 2000;64:292–303.

    Article  CAS  PubMed  Google Scholar 

  25. Gambari R, Fibach E. Medicinal chemistry of fetal hemoglobin inducers for treatment of β-thalassemia. Curr Med Chem. 2007;14:199–212.

    Article  CAS  PubMed  Google Scholar 

  26. Zuccato C, Bianchi N, Borgatti M, Lampronti I, Massei F, Favre C, et al. Everolimus is a potent inducer of erythroid differentiation and gamma-globin gene expression in human erythroid cells. Acta Haematol. 2007;117:168–76.

    Article  CAS  PubMed  Google Scholar 

  27. Fibach E, Bianchi N, Borgatti M, Prus E, Gambari R. Mithramycin induces fetal hemoglobin production in normal and thalassemic human erythroid precursor cells. Blood. 2003;102:1276–81.

    Article  CAS  PubMed  Google Scholar 

  28. Fibach E, Bianchi N, Borgatti M, Zuccato C, Finotti A, Lampronti I, et al. Effects of rapamycin on accumulation of alpha-, beta- and gamma-globin mRNAs in erythroid precursor cells from β-thalassaemia patients. Eur J Haematol. 2006;77:437–41.

    Article  CAS  PubMed  Google Scholar 

  29. Quentmeier H, Zaborski M, Drexler HG. The human bladder carcinoma cell line 5637 constitutively secretes functional cytokines. Leuk Res. 1997;21:343–50.

    Article  CAS  PubMed  Google Scholar 

  30. Penolazzi L, Lambertini E, Borgatti M, Piva R, Cozzani M, Giovannini I, et al. Decoy oligodeoxynucleotides targeting NF-kappa B transcription factors: induction of apoptosis in human primary osteoclasts. Biochem Pharmacol. 2003;66:1189–98.

    Article  CAS  PubMed  Google Scholar 

  31. Piva R, Penolazzi L, Zennaro M, Bianchini E, Magri E, Borgatti M, et al. Induction of apoptosis of osteoclasts by targeting transcription factors with decoy molecules. Ann N Y Acad Sci. 2006;1091:509–16. Review.

    Article  CAS  PubMed  Google Scholar 

  32. Lampronti I, Martello D, Bianchi N, Borgatti M, Lambertini E, Piva R, et al. In vitro antiproliferative effects on human tumor cell lines of extracts from the Bangladeshi medicinal plant Aegle marmelos Correa. Phytomedicine. 2003;10:300–8.

    Article  CAS  PubMed  Google Scholar 

  33. Bianchi N, Zuccato C, Lampronti I, Borgatti M, Gambari R. 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. 2009;6:141–51.

    Article  PubMed  Google Scholar 

  34. Parrish JA. Phototherapy and photochemotherapy of skin diseases. J Invest Dermatol. 1981;77:167–71.

    Article  CAS  PubMed  Google Scholar 

  35. Cristofolini M, Recchia G, Boi S, Piscioli F, Bordin F, Baccichetti F, et al. 6-Methylangelicins: new monofunctional photochemotherapeutic agents for psoriasis. Br J Dermatol. 1990;122:513–24.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

R.G. is granted by AIRC, Fondazione Cariparo (Cassa di Risparmio di Padova e Rovigo), Cofin-2005, by STAMINA Project (University of Ferrara), by UE ITHANET Project and by Telethon Project (GGP07257). This research was also supported by Regione Emilia–Romagna (Spinner Project) and by Associazione Veneta per la Lotta alla Talassemia, Rovigo.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Ferrara, Via Fossato di Mortara, 74, 44100, Ferrara, Italy

    Ilaria Lampronti, Nicoletta Bianchi, Cristina Zuccato, Giulia Breveglieri, Monica Borgatti, Alessia Finotti, Giordana Feriotto, Francesca Salvatori & Roberto Gambari

  2. Department of Pharmaceutical Sciences, University of Padova, Padova, Italy

    Francesco Dall’Acqua, Daniela Vedaldi & Giampietro Viola

  3. S.I.T. ULSS 18, Rovigo, Servizio di Immunoematologia e Trasfusione, Rovigo, Italy

    Rocco Potenza & Francesco Chiavilli

Authors
  1. Ilaria Lampronti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicoletta Bianchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cristina Zuccato
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francesco Dall’Acqua
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniela Vedaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giampietro Viola
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rocco Potenza
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francesco Chiavilli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giulia Breveglieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Monica Borgatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alessia Finotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Giordana Feriotto
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Francesca Salvatori
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Roberto Gambari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberto Gambari.

About this article

Cite this article

Lampronti, I., Bianchi, N., Zuccato, C. et al. Increase in γ-globin mRNA content in human erythroid cells treated with angelicin analogs. Int J Hematol 90, 318–327 (2009). https://doi.org/10.1007/s12185-009-0422-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-009-0422-2

Keywords

Search

Navigation