Open Access

Parthenolide induces apoptosis and lytic cytotoxicity in Epstein-Barr virus-positive Burkitt lymphoma

  • Authors:
    • Yuan Li
    • Yongli Zhang
    • Mingming Fu
    • Qin Yao
    • Huiqin Zhuo
    • Quanyi Lu
    • Xiaoqing Niu
    • Peng Zhang
    • Yihua Pei
    • Kejie Zhang
  • View Affiliations

  • Published online on: June 20, 2012     https://doi.org/10.3892/mmr.2012.959
  • Pages: 477-482
  • Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Burkitt lymphoma (BL) has been reported to be strongly associated with Epstein-Barr virus (EBV) infection. The fact that EBV is generally present in cancer cells but rarely found in healthy cells represents an opportunity for targeted cancer therapy. One approach is to activate the lytic replication cycle of the latent EBV. Nuclear factor (NF)-κB is thought to play an essential role in EBV lytic infection. Elevated NF-κB levels inhibit EBV lytic replication. Parthenolide (PN) is a sesquiterpene lactone found in medicinal plants, particularly in feverfew (Tanacetum parthenium). The aim of the present study was to analyze the effect of PN on the survival of Raji EBV-positive lymphoma cells. Raji cells were treated with 0, 4 or 6 µmol/l PN for 48 h. MTT assay and western blot analysis were performed to evaluate the findings. Results showd that PN suppressed the growth of the EBV-positive BL cell line, Raji, and activated the transcription of BZLF1 and BRLF1 by inhibiting NF-κB activity. Most notably, when PN was used in combination with ganciclovir (GCV), the cytotoxic effect of PN was amplified. These data suggest that the induction of lytic EBV infection with PN in combination with GCV may be a viral‑targeted therapy for EBV-associated BL.

References

1 

Yang L, Parkin DM, Whelan S, Zhang S, Chen Y, Lu F and Li L: Statistics on cancer in China: cancer registration in 2002. Eur J Cancer Prev. 14:329–335. 2005. View Article : Google Scholar : PubMed/NCBI

2 

Parkin DM: The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 118:3030–3044. 2006.PubMed/NCBI

3 

Cohen JI, Kimura H, Nakamura S, Ko YH and Jaffe ES: Epstein-Barr virus-associated lymphoproliferative disease in non-immunocompromised hosts: a status report and summary of an international meeting, 8–9 September 2008. Ann Oncol. 20:1472–1482. 2009.PubMed/NCBI

4 

Thorley-Lawson DA and Gross A: Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med. 350:1328–1337. 2004. View Article : Google Scholar : PubMed/NCBI

5 

Thorley-Lawson DA and Allday MJ: The curious case of the tumour virus: 50 years of Burkitt’s lymphoma. Nat Rev Microbiol. 6:913–924. 2008.PubMed/NCBI

6 

Cohen JI, Bollard CM, Khanna R and Pittaluga S: Current understanding of the role of Epstein-Barr virus in lymphomagenesis and therapeutic approaches to EBV-associated lymphomas. Leuk Lymphoma. 49(Suppl 1): 27–34. 2008. View Article : Google Scholar : PubMed/NCBI

7 

Perrine SP, Hermine O, Small T, et al: A phase 1/2 trial of arginine butyrate and ganciclovir in patients with Epstein-Barr virus-associated lymphoid malignancies. Blood. 109:2571–2578. 2007. View Article : Google Scholar : PubMed/NCBI

8 

Fu DX, Tanhehco Y, Chen J, et al: Bortezomib-induced enzyme-targeted radiation therapy in herpesvirus-associated tumors. Nat Med. 14:1118–1122. 2008. View Article : Google Scholar : PubMed/NCBI

9 

Landais E, Saulquin X, Scotet E, et al: Direct killing of Epstein-Barr virus (EBV)-infected B cells by CD4 T cells directed against the EBV lytic protein BHRF1. Blood. 103:1408–1416. 2004. View Article : Google Scholar : PubMed/NCBI

10 

Feng WH, Israel B, Raab-Traub N, Busson P and Kenney SC: Chemotherapy induces lytic EBV replication and confers ganciclovir susceptibility to EBV-positive epithelial cell tumors. Cancer Res. 62:1920–1926. 2002.PubMed/NCBI

11 

Hailfinger S, Nogai H, Pelzer C, et al: Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines. Proc Natl Acad Sci USA. 108:14596–14601. 2011. View Article : Google Scholar : PubMed/NCBI

12 

Song YJ and Kang MS: Roles of TRAF2 and TRAF3 in Epstein-Barr virus latent membrane protein 1-induced alternative NF-kappaB activation. Virus Genes. 41:174–180. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Cahir-McFarland ED, Davidson DM, Schauer SL, Duong J and Kieff E: NF-kappa B inhibition causes spontaneous apoptosis in Epstein-Barr virus-transformed lymphoblastoid cells. Proc Natl Acad Sci USA. 97:6055–6060. 2000. View Article : Google Scholar

14 

Chaudhary PM, Jasmin A, Eby MT and Hood L: Modulation of the NF-kappa B pathway by virally encoded death effector domains-containing proteins. Oncogene. 18:5738–5746. 1999. View Article : Google Scholar : PubMed/NCBI

15 

Izumi KM and Kieff ED: The Epstein-Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF-kappaB. Proc Natl Acad Sci USA. 94:12592–12597. 1997. View Article : Google Scholar

16 

Keller SA, Schattner EJ and Cesarman E: Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells. Blood. 96:2537–2542. 2000.PubMed/NCBI

17 

Smolinski AT and Pestka JJ: Comparative effects of the herbal constituent parthenolide (Feverfew) on lipopolysaccharide-induced inflammatory gene expression in murine spleen and liver. J Inflamm (Lond). 2:62005. View Article : Google Scholar

18 

Pareek A, Suthar M, Rathore GS and Bansal V: Feverfew (Tanacetum parthenium L.): A systematic review. Pharmacogn Rev. 5:103–110. 2011.

19 

deGraffenried LA, Chandrasekar B, Friedrichs WE, et al: NF-kappa B inhibition markedly enhances sensitivity of resistant breast cancer tumor cells to tamoxifen. Ann Oncol. 15:885–890. 2004. View Article : Google Scholar : PubMed/NCBI

20 

Nakshatri H, Rice SE and Bhat-Nakshatri P: Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase. Oncogene. 23:7330–7344. 2004. View Article : Google Scholar

21 

Dai Y, Guzman ML, Chen S, et al: The NF (Nuclear factor)-kappaB inhibitor parthenolide interacts with histone deacetylase inhibitors to induce MKK7/JNK1-dependent apoptosis in human acute myeloid leukaemia cells. Br J Haematol. 151:70–83. 2010. View Article : Google Scholar

22 

Israel BF and Kenney SC: Virally targeted therapies for EBV-associated malignancies. Oncogene. 22:5122–5130. 2003. View Article : Google Scholar : PubMed/NCBI

23 

Flemington EK: Herpesvirus lytic replication and the cell cycle: arresting new developments. J Virol. 75:4475–4481. 2001. View Article : Google Scholar : PubMed/NCBI

24 

Wang H, Zhao Y, Zeng L, Tang M, El-Deeb A, Li JJ and Cao Y: BZLF1 controlled by family repeat domain induces lytic cytotoxicity in Epstein-Barr virus-positive tumor cells. Anticancer Res. 24:67–74. 2004.PubMed/NCBI

25 

Chen YL, Law PY and Loh HH: Inhibition of PI3K/Akt signaling: an emerging paradigm for targeted cancer therapy. Curr Med Chem Anticancer Agents. 5:575–589. 2005. View Article : Google Scholar : PubMed/NCBI

26 

Feng WH and Kenney SC: Valproic acid enhances the efficacy of chemotherapy in EBV-positive tumors by increasing lytic viral gene expression. Cancer Res. 66:8762–8769. 2006. View Article : Google Scholar : PubMed/NCBI

27 

Urier G, Buisson M, Chambard P and Sergeant A: The Epstein-Barr virus early protein EB1 activates transcription from different responsive elements including AP-1 binding sites. EMBO J. 8:1447–1453. 1989.PubMed/NCBI

28 

Zalani S, Holley-Guthrie E and Kenney S: Epstein-Barr viral latency is disrupted by the immediate-early BRLF1 protein through a cell-specific mechanism. Proc Natl Acad Sci USA. 93:9194–9199. 1996. View Article : Google Scholar : PubMed/NCBI

29 

Mogensen TH and Paludan SR: Molecular pathways in virus-induced cytokine production. Microbiol Mol Biol Rev. 65:131–150. 2001. View Article : Google Scholar : PubMed/NCBI

30 

Hiscott J, Kwon H and Genin P: Hostile takeovers: viral appropriation of the NF-kappaB pathway. J Clin Invest. 107:143–151. 2001. View Article : Google Scholar : PubMed/NCBI

31 

Santoro MG, Rossi A and Amici C: NF-kappaB and virus infection: who controls whom. EMBO J. 22:2552–2560. 2003. View Article : Google Scholar : PubMed/NCBI

32 

Brown HJ, Song MJ, Deng H, Wu TT, Cheng G and Sun R: NF-kappaB inhibits gammaherpesvirus lytic replication. J Virol. 77:8532–8540. 2003. View Article : Google Scholar : PubMed/NCBI

33 

Kwok BH, Koh B, Ndubuisi MI, Elofsson M and Crews CM: The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. Chem Biol. 8:759–766. 2001. View Article : Google Scholar : PubMed/NCBI

34 

Hayashi S, Koshiba K, Hatashita M, et al: Thermosensitization and induction of apoptosis or cell-cycle arrest human prostate cancer androgen-independent cell lines. Int J Mol Med. 28:1033–1042. 2011.PubMed/NCBI

35 

Gunn EJ, Williams JT, Huynh DT, et al: The natural products parthenolide and andrographolide exhibit anti-cancer stem cell activity in multiple myeloma. Leuk Lymphoma. 52:1085–1097. 2011. View Article : Google Scholar : PubMed/NCBI

36 

Ghashghaeinia M, Toulany M, Saki M, et al: The NFkB pathway inhibitors Bay 11-7082 and parthenolide induce programmed cell death in anucleated Erythrocytes. Cell Physiol Biochem. 27:45–54. 2011. View Article : Google Scholar : PubMed/NCBI

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September 2012
Volume 6 Issue 3

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Copy and paste a formatted citation
APA
Li, Y., Zhang, Y., Fu, M., Yao, Q., Zhuo, H., Lu, Q. ... Zhang, K. (2012). Parthenolide induces apoptosis and lytic cytotoxicity in Epstein-Barr virus-positive Burkitt lymphoma. Molecular Medicine Reports, 6, 477-482. https://doi.org/10.3892/mmr.2012.959
MLA
Li, Y., Zhang, Y., Fu, M., Yao, Q., Zhuo, H., Lu, Q., Niu, X., Zhang, P., Pei, Y., Zhang, K."Parthenolide induces apoptosis and lytic cytotoxicity in Epstein-Barr virus-positive Burkitt lymphoma". Molecular Medicine Reports 6.3 (2012): 477-482.
Chicago
Li, Y., Zhang, Y., Fu, M., Yao, Q., Zhuo, H., Lu, Q., Niu, X., Zhang, P., Pei, Y., Zhang, K."Parthenolide induces apoptosis and lytic cytotoxicity in Epstein-Barr virus-positive Burkitt lymphoma". Molecular Medicine Reports 6, no. 3 (2012): 477-482. https://doi.org/10.3892/mmr.2012.959