International Journal of Hematology

, Volume 92, Issue 1, pp 136–143

Ellagic acid, a natural polyphenolic compound, induces apoptosis and potentiates retinoic acid-induced differentiation of human leukemia HL-60 cells

  • Yuki Hagiwara
  • Takashi Kasukabe
  • Yasuhiko Kaneko
  • Nozomi Niitsu
  • Junko Okabe-Kado
Original Article

Abstract

All-trans retinoic acid (ATRA) is a standard drug used for differentiation therapy in acute promyelocytic leukemia. To potentiate this therapy, we examined the effect of ellagic acid (EA), a natural polyphenolic compound with antiproliferative and antioxidant properties, on the growth and differentiation of HL-60 acute myeloid leukemia cells. EA was found to induce apoptosis, which was blocked by pan-caspase inhibitor, Z-VAD-FMK. EA activated the caspase-3 pathway and enhanced the expressions of myeloid differentiation markers (CD11b, MRP-14 protein, granulocytic morphology) induced by ATRA treatment. These results indicate that EA is a potent apoptosis inducer and also effectively potentiates ATRA-induced myeloid differentiation of HL-60 cells.

Keywords

Ellagic acid Acute myeloid leukemia cells Apoptosis Caspase Differentiation ATRA 

References

  1. 1.
    Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid leukemia. Blood. 2005;106:1154–63.CrossRefPubMedGoogle Scholar
  2. 2.
    Honma Y. Cotylenin A—a plant growth regulator as a differentiation inducing agent against myeloid leukemia. Leuk Lymphoma. 2002;43(6):1169–78.CrossRefPubMedGoogle Scholar
  3. 3.
    Dorai T, Aggarwal BB. Role of chemopreventive agents in cancer therapy. Cancer Lett. 2004;215:129–40.CrossRefPubMedGoogle Scholar
  4. 4.
    Seeram NP, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG, Heber D. In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. J Nutr Biochem. 2005;16:360–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Stoner GD, Mukhtar H. Polyphenols as cancer chemopreventive agents. J Cell Biochem Suppl. 1995;22:169–80.CrossRefPubMedGoogle Scholar
  6. 6.
    Festa F, Aglitti T, Duranti G, Ricordy R, Perticone P, Cozzi R. Strong antioxidant activity of ellagic acid in mammalian cells in vitro revealed by the comet assay. Anticancer Res. 2001;21(6A):3903–8.PubMedGoogle Scholar
  7. 7.
    Banzouzi JT, Prado R, Menan H, Valenin A, Roumestan C, Mallie M, Pellissier Y, Blache Y. In vitro antiplasmodial activity of extracts of Alchornea cordifolia and identification of an active constituent: ellagic acid. J Ethnopharmacol. 2002;81(3):399–401.CrossRefPubMedGoogle Scholar
  8. 8.
    Aiyer HS, Vadhanam MV, Stoyanova R, Caprio GD, Clapper ML, Gupta RC. Dietary berries and ellagic acid prevent oxidative DNA damage and modulate expression of DNA repair genes. Int J Mol Sci. 2008;9(3):327–41.CrossRefPubMedGoogle Scholar
  9. 9.
    Han DH, Lee MJ, Kim JH. Antioxidant and apoptosis-inducing activities of ellagic acid. Anticancer Res. 2006;26(5A):3601–6.PubMedGoogle Scholar
  10. 10.
    Losso JN, Bansode RR, Trappey A 2nd, Bawadi HA, Truax R. In vitro anti-proliferative activities of ellagic acid. J Nutr Biochem. 2004;15(11):672–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Edderkaoui M, Odinokova I, Ohno I, Gukovsky I, Go VL, Pandol SJ, Gukovskaya AS. Ellagic acid induces apoptosis through inhibition of nuclear factor kappa B in pancreatic cancer cells. World J Gastroenterol. 2008;14(23):3672–80.CrossRefPubMedGoogle Scholar
  12. 12.
    Li TM, Chen GW, Su CC, Yeh CC, Cheng KC, Chung JG. Ellagic acid induced p53/p21 expression, G1 arrest and apoptosis in human bladder cancer T24 cells. Anticancer Res. 2005;25(2A):971–9.PubMedGoogle Scholar
  13. 13.
    Larrosa M, Thomás-Barberán FA, Espín JC. The dietary hydrolysable tannin punicalagin releases ellagic acid that induces apoptosis in human colon adenocarcinoma Caco-2 cells by using the mitochondrial pathway. J Nutr Biochem. 2006;17(9):611–25.CrossRefPubMedGoogle Scholar
  14. 14.
    Narayanan BA, Geoffroy O, Willingham MC, Re GG, Nixon DW. p53/p21 (WAF1/CIP1) expression and its possible role of in G1 arrest and apoptosis in ellagic acid treated cancer cells. Cancer Lett. 1999;136(2):215–21.CrossRefPubMedGoogle Scholar
  15. 15.
    Mertens-Talcott SU, Talcott ST, Percival SS. Low concentrations of quercetin and ellagic acid synergistically influence proliferation, cytotoxicity and apoptosis in MOLT-4 human leukemia cells. J Nutr. 2003;133(8):2669–74.PubMedGoogle Scholar
  16. 16.
    Nuňez G, Benedict MA, Hu Y, Inohara N. Caspases: the proteases of the apoptotic pathway. Oncogene. 1998;17(25):3237–45.PubMedGoogle Scholar
  17. 17.
    Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science. 1998;281(5381):1305–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer. 2002;2(6):420–30.CrossRefPubMedGoogle Scholar
  19. 19.
    Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest. 1999;104(2):155–62.CrossRefPubMedGoogle Scholar
  20. 20.
    Lawrence D, Shahrokh Z, Marsters S, Achilles K, Shih D, Mounho B, et al. Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med. 2001;7(4):383–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Gazitt Y. TRAIL is a potent inducer of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells. Leukemia. 1999;13(11):1817–24.CrossRefPubMedGoogle Scholar
  22. 22.
    Pollack IF, Erff M, Ashkenazi A. Direct stimulation of apoptotic signaling by soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand leads to selective killing of glioma cells. Clin Cancer Res. 2001;7(5):1362–9.PubMedGoogle Scholar
  23. 23.
    Qin J, Chaturvedi V, Bonish B, Nickoloff BJ. Avoiding premature apoptosis of normal epidermal cells. Nat Med. 2001;7(4):385–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Ashkenazi A, Holland P, Eckhardt SG. Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). J Clin Oncol. 2008;26(21):3621–30.CrossRefPubMedGoogle Scholar
  25. 25.
    Fjaeraa C, Nånberg E. Effect of ellagic acid on proliferation, cell adhesion and apoptosis in SH-SY5Y human neuroblastoma cells. Biomed Pharmacother. 2009;63(4):254–61.CrossRefPubMedGoogle Scholar
  26. 26.
    Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berqer R, Fenaux P, Deqos L. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood. 1990;76(9):1704–9.PubMedGoogle Scholar
  27. 27.
    Yokoyama A, Okabe-Kado J, Wakimoto N, et al. Evaluation by multivariate analysis of the differentiation inhibitory factor nm23 as a prognostic factor in acute myelogenous leukemia and application to other hematological malignancies. Blood. 1998;91:1845–51.PubMedGoogle Scholar
  28. 28.
    Rumjahn SM, Javed MA, Wong N, Law WE, Buxton ILO. Purinergic regulation of angiogenesis by human breast carcinoma-secreted nucleoside diphosphate kinase. Br J Cancer. 2007;97:1372–80.CrossRefPubMedGoogle Scholar
  29. 29.
    Khanduja KL, Avti PK, Kumar S, Mittal N, Sohi KK, Pathak CM. Anti-apoptotic activity of caffeic acid, ellagic acid and ferulic acid in normal human peripheral blood mononuclear cells: a Bcl-2 independent mechanism. Biochem Biophys Acta. 2006;1760(2):283–9.PubMedGoogle Scholar
  30. 30.
    Tasaki M, Uemura T, Maeda M, Ishii Y, Okamura T, Inoue T, et al. Safety assessment of ellagic acid, a food additive, in a subchronic toxicity study using F344 rats. Food Chem Toxicol. 2008;46(3):1119–24.PubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2010

Authors and Affiliations

  • Yuki Hagiwara
    • 1
    • 2
  • Takashi Kasukabe
    • 1
  • Yasuhiko Kaneko
    • 1
  • Nozomi Niitsu
    • 2
  • Junko Okabe-Kado
    • 1
  1. 1.Research Institute for Clinical OncologySaitama Cancer CenterKitaadachi-gunJapan
  2. 2.Department of Hematology, Comprehensive Cancer Center, International Medical CenterSaitama Medical UniversityHidakaJapan

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