Medical Oncology

, Volume 27, Issue 4, pp 1096–1101 | Cite as

Cell cycle inhibition and apoptosis induced by curcumin in Ewing sarcoma cell line SK-NEP-1

  • Mansher Singh
  • Ambarish Pandey
  • Collins A. Karikari
  • Gayatri Singh
  • Dinesh Rakheja
Original Paper

Abstract

Curcumin is a naturally occurring polyphenolic compound found in the turmeric, which is used as food additive in Indian cooking and as a therapeutic agent in traditional Indian medicine. Curcumin is currently under investigation as a chemotherapeutic and chemopreventive agent in adult cancer models at both pre-clinical and clinical levels. In this preliminary study, we show that curcumin is effective in causing cell cycle arrest, inducing apoptosis, and suppressing colony formation in the Ewing sarcoma cell line SK-NEP-1. Curcumin causes upregulation of cleaved caspase 3 and downregulation of phospho-Akt, producing apoptosis in Ewing sarcoma cells at an inhibitory concentration 50% (IC50) of approximately 4 μM. Our findings indicate a need for further evaluation of curcumin in chemotherapy and chemoprevention of Ewing sarcoma.

Keywords

Curcumin Ewing sarcoma Apoptosis 

References

  1. 1.
    Khoury JD. Ewing sarcoma family of tumors. Adv Anat Pathol. 2005;12:212–20.PubMedCrossRefGoogle Scholar
  2. 2.
    Delattre O, Zucman J, Plougastel B, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992;359:162–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348:694–701.PubMedCrossRefGoogle Scholar
  4. 4.
    Hawkins D, Barnett T, Bensinger W, Gooley T, Sanders J. Busulfan, melphalan, and thiotepa with or without total marrow irradiation with hematopoietic stem cell rescue for poor-risk Ewing-Sarcoma-Family tumors. Med Pediatr Oncol. 2000;34:328–37.PubMedCrossRefGoogle Scholar
  5. 5.
    Burchill SA. Molecular abnormalities in Ewing’s sarcoma. Expert Rev Anticancer Ther. 2008;8:1675–87.PubMedCrossRefGoogle Scholar
  6. 6.
    Kontny U. Regulation of apoptosis and proliferation in Ewing’s sarcoma—opportunities for targeted therapy. Hematol Oncol. 2006;24:14–21.PubMedCrossRefGoogle Scholar
  7. 7.
    Windsor R, Strauss S, Seddon B, Whelan J. Experimental therapies in Ewing’s sarcoma. Expert Opin Investig Drugs. 2009;18:143–59.PubMedCrossRefGoogle Scholar
  8. 8.
    Afaq F, Adhami VM, Ahmad N, Mukhtar H. Botanical antioxidants for chemoprevention of photocarcinogenesis. Front Biosci. 2002;7:d784–92.PubMedCrossRefGoogle Scholar
  9. 9.
    Eigner D, Scholz D. Ferula asa-foetida and Curcuma longa in traditional medical treatment and diet in Nepal. J Ethnopharmacol. 1999;67:1–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Han R. Highlight on the studies of anticancer drugs derived from plants in China. Stem Cells. 1994;12:53–63.PubMedCrossRefGoogle Scholar
  11. 11.
    Lodha R, Bagga A. Traditional Indian systems of medicine. Ann Acad Med Singap. 2000;29:37–41.PubMedGoogle Scholar
  12. 12.
    Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 2003;23:363–98.PubMedGoogle Scholar
  13. 13.
    Shishodia S, Sethi G, Aggarwal BB. Curcumin: getting back to the roots. Ann N Y Acad Sci. 2005;1056:206–17.PubMedCrossRefGoogle Scholar
  14. 14.
    Sharma RA, Euden SA, Platton SL, et al. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin Cancer Res. 2004;10:6847–54.PubMedCrossRefGoogle Scholar
  15. 15.
    Sharma RA, McLelland HR, Hill KA, et al. Pharmacodynamic and pharmacokinetic study of oral curcuma extract in patients with colorectal cancer. Clin Cancer Res. 2001;7:1894–900.PubMedGoogle Scholar
  16. 16.
    Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol Pharmacol. 2006;69:195–206.PubMedGoogle Scholar
  17. 17.
    Aggarwal S, Takada Y, Singh S, Myers JN, Aggarwal BB. Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-kappaB signaling. Int J Cancer. 2004;111:679–92.PubMedCrossRefGoogle Scholar
  18. 18.
    Bharti AC, Donato N, Singh S, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood. 2003;101:1053–62.PubMedCrossRefGoogle Scholar
  19. 19.
    Bava SV, Puliappadamba VT, Deepti A, Nair A, Karunagaran D, Anto RJ. Sensitization of taxol-induced apoptosis by curcumin involves down-regulation of nuclear factor-kappaB and the serine/threonine kinase Akt and is independent of tubulin polymerization. J Biol Chem. 2005;280:6301–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Beevers CS, Li F, Liu L, Huang S. Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells. Int J Cancer. 2006;119:757–64.PubMedCrossRefGoogle Scholar
  21. 21.
    Smith MA, Morton CL, Phelps D, Girtman K, Neale G, Houghton PJ. SK-NEP-1 and Rh1 are Ewing family tumor lines. Pediatr Blood Cancer. 2008;50:703–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Martelli AM, Faenza I, Billi AM, et al. Intranuclear 3′-phosphoinositide metabolism and Akt signaling: new mechanisms for tumorigenesis and protection against apoptosis? Cell Signal. 2006;18:1101–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis. 2004;9:667–76.PubMedCrossRefGoogle Scholar
  24. 24.
    Lambert JD, Hong J, Yang GY, Liao J, Yang CS. Inhibition of carcinogenesis by polyphenols: evidence from laboratory investigations. Am J Clin Nutr. 2005;81:284S–91S.PubMedGoogle Scholar
  25. 25.
    Arbiser JL, Klauber N, Rohan R, et al. Curcumin is an in vivo inhibitor of angiogenesis. Mol Med. 1998;4:376–83.PubMedGoogle Scholar
  26. 26.
    Jovanovic SV, Boone CW, Steenken S, Trinoga M, Kaskey RB. How curcumin works preferentially with water soluble antioxidants. J Am Chem Soc. 2001;123:3064–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Thaloor D, Singh AK, Sidhu GS, Prasad PV, Kleinman HK, Maheshwari RK. Inhibition of angiogenic differentiation of human umbilical vein endothelial cells by curcumin. Cell Growth Differ. 1998;9:305–12.PubMedGoogle Scholar
  28. 28.
    Ramachandran C, You W. Differential sensitivity of human mammary epithelial and breast carcinoma cell lines to curcumin. Breast Cancer Res Treat. 1999;54:269–78.PubMedCrossRefGoogle Scholar
  29. 29.
    Jiang MC, Yang-Yen HF, Yen JJ, Lin JK. Curcumin induces apoptosis in immortalized NIH 3T3 and malignant cancer cell lines. Nutr Cancer. 1996;26:111–20.PubMedCrossRefGoogle Scholar
  30. 30.
    Syng-Ai C, Kumari AL, Khar A. Effect of curcumin on normal and tumor cells: role of glutathione and bcl-2. Mol Cancer Ther. 2004;3:1101–8.PubMedGoogle Scholar
  31. 31.
    Nozawa S, Ohno T, Banno Y, et al. Inhibition of platelet-derived growth factor-induced cell growth signaling by a short interfering RNA for EWS-Fli1 via down-regulation of phospholipase D2 in Ewing sarcoma cells. J Biol Chem. 2005;280:27544–51.PubMedCrossRefGoogle Scholar
  32. 32.
    Hussain AR, Al-Rasheed M, Manogaran PS, et al. Curcumin induces apoptosis via inhibition of PI3′-kinase/AKT pathway in acute T cell leukemias. Apoptosis. 2006;11:245–54.PubMedCrossRefGoogle Scholar
  33. 33.
    Tomita M, Kawakami H, Uchihara JN, et al. Curcumin (diferuloylmethane) inhibits constitutive active NF-kappaB, leading to suppression of cell growth of human T-cell leukemia virus type I-infected T-cell lines and primary adult T-cell leukemia cells. Int J Cancer. 2006;118:765–72.PubMedCrossRefGoogle Scholar
  34. 34.
    Shishodia S, Amin HM, Lai R, Aggarwal BB. Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma. Biochem Pharmacol. 2005;70:700–13.PubMedCrossRefGoogle Scholar
  35. 35.
    Woo JH, Kim YH, Choi YJ, et al. Molecular mechanisms of curcumin-induced cytotoxicity: induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt. Carcinogenesis. 2003;24:1199–208.PubMedCrossRefGoogle Scholar
  36. 36.
    Squires MS, Hudson EA, Howells L, et al. Relevance of mitogen activated protein kinase (MAPK) and phosphotidylinositol-3-kinase/protein kinase B (PI3K/PKB) pathways to induction of apoptosis by curcumin in breast cells. Biochem Pharmacol. 2003;65:361–76.PubMedCrossRefGoogle Scholar
  37. 37.
    Tong QS, Zheng LD, Lu P, et al. Apoptosis-inducing effects of curcumin derivatives in human bladder cancer cells. Anticancer Drugs. 2006;17:279–87.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Mansher Singh
    • 1
  • Ambarish Pandey
    • 1
  • Collins A. Karikari
    • 2
  • Gayatri Singh
    • 1
  • Dinesh Rakheja
    • 3
    • 4
  1. 1.All India Institute of Medical SciencesNew DelhiIndia
  2. 2.Department of Pathology, The Sol Goldman Pancreatic Cancer Research CenterJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of PathologyChildren’s Medical CenterDallasUSA
  4. 4.University of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations