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

Li,Yuan; Zhang,Yongli; Fu,Mingming; Yao,Qin; Zhuo,Huiqin; Lu,Quanyi; Niu,Xiaoqing; Zhang,Peng; Pei,Yihua; Zhang,Kejie

doi:10.3892/mmr.2012.959

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

Affiliations: Department of Hematology, Zhongshan Hospital, Xiamen University, Fujian Medical University Clinic Teaching Hospital, Xiamen 361004, P.R. China, Department of Emergency Surgery, Zhongshan Hospital, Xiamen University, Fujian Medical University Clinic Teaching Hospital, Xiamen 361004, P.R. China, Central Laboratory, Zhongshan Hospital, Xiamen University, Fujian Medical University Clinic Teaching Hospital, Xiamen 361004, P.R. China
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].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View 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