Tumor Biology

, Volume 37, Issue 1, pp 531–539 | Cite as

Synergistic action of 5Z-7-oxozeaenol and bortezomib in inducing apoptosis of Burkitt lymphoma cell line Daudi

  • Jie Zhang
  • Bing Li
  • Haixia Wu
  • Jiayao Ou
  • Rongbin Wei
  • Junjun Liu
  • Wenping Cai
  • Xiaodong Liu
  • Shouliang Zhao
  • Jianhua Yang
  • Lili Zhou
  • Shangfeng Liu
  • Aibin Liang
Original Article

Abstract

Treatment failure in cancer chemotherapy is largely due to the toxic effects of chemotherapeutic agents on normal cells/tissues. The proteasome inhibitor bortezomib has been successfully applied to treat multiple myeloma (MM), but there are some common adverse reactions in the clinic including peripheral neuropathy (PN). The TAK1 selective inhibitor 5Z-7-oxozeaenol has been widely studied in cancer therapy. Here, we investigated the potential synergy of bortezomib and 5Z-7-oxozeaenol in Burkitt’s lymphoma (BL) cell lines. Cell viability assay showed that co-treatment of bortezomib at 8 nM, representing a one-eighth concentration for growth arrest, and 5Z-7-oxozeaenol at 2 μM, a dose that exhibited insignificant cytotoxic effects, synergistically induced apoptosis in the cell line Daudi. In parallel with the increasing dose of the bortezomib, and 5Z-7-oxozeaenol at 0.5 μM, lower colony formation efficiencies were seen in the cell line Daudi. Western blotting analysis verified that TAK1 inhibition by 5Z-7-oxozeaenol completely blocked JNK, p38, Erk, IKK, and IκB phosphorylation, which was almost instantly activated by TAK1 both directly or indirectly. Both agents synergistically prevented nuclear translocation of NF-κB, a characteristic of NF-κB inactivation. Moreover, a synergistic effect of bortezomib and 5Z-7-oxozeaenol on Western blotting analysis and flow cytometry was disclosed. Collectively, our results indicated that the proteasome inhibitor bortezomib and the TAK1 inhibitor 5Z-7-oxozeaenol displayed synergy on inhibiting BL cell apoptosis by inhibiting NF-κB activity.

Keywords

NF-κB Bortezomib 5Z-7-oxozeaenol TAK1 Burkitt’s lymphoma 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81270615), and the Outstanding Discipline Leaders of Shanghai Health System Support Program (XBR2013077).

Conflicts of interest

No conflict of interest exits in the submission of this manuscript, and the manuscript is approved by all authors for publication. I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part.

Author contributions

J. Z. and B. L.: manuscript writing and editing; H. W., J. O., R. W., J. L., W. C., X. L., S. Z., J. Y., and L. Z.: critical discussion for conception and design; S. L. and A. L.: conception and design, manuscript writing and editing, and final approval of manuscript.

Supplementary material

13277_2015_3832_MOESM1_ESM.pptx (101 kb)
Fig. S1 5Z-7-oxozeaenol enhances the cytotoxic effect of bortezomib on Burkitt lymphoma cell Daudi. Daudi cells were seeded into 96-well plates at a concentration of 1.5 × 104/well. After 16 h, cells were incubated with drugs combinational or respective for 24/48/72/96 h at indicated concentrations and cell viability was assessed by CCK-8 assay. Results presented as % vehicle ± SD (n = 5). ***P ≤ 0.001, **P ≤ 0.01, *P ≤ 0.05 (Student’s t test, two-tailed) (PPTX 100 kb)
13277_2015_3832_MOESM2_ESM.pptx (78 kb)
Fig. S2 Cytotoxic effect of 5Z-7-oxozeaenol and bortezomib on Burkitt lymphoma cells Raji or NAMALWA. Raji or NAMALWA cells were seeded in 96-well plates at a concentration of 1.5 × 104 cells per well. After 16 h, cells were incubated with drugs for 24 h at indicated concentrations, and growth inhibition was assessed by CCK-8 assay. Results presented as % vehicle ± SD (n = 5). P > 0.05 (Student’s t test, two-tailed) (PPTX 78 kb)
13277_2015_3832_MOESM3_ESM.pptx (88 kb)
Fig. S3 5Z-7-oxozeaenol inhibits Erk, p38 activation in Daudi. Daudi cells were treated with bortezomib at the indicated time points (0, 2, 5, 10, 15 min) with or without 5Z-7-oxozeaenol, total protein extracts were subjected to SDS-PAGE and immunoblotted with antibodies indicated. β-tubulin was detected as a loading control for whole cell extracts (PPTX 87 kb)
13277_2015_3832_MOESM4_ESM.pptx (234 kb)
Fig. S4 BaF-3 cells were treated with bortezomib (8 nM) and 5Z-7-oxozeaenol (2 μM) for 24/48 h and examined by flow cytometry using Annexin-V/PI staining to label apoptotic cells (PPTX 233 kb)

References

  1. 1.
    Molyneux EM, Rochford R, Griffin B, et al. Burkitt's lymphoma. Lancet. 2012;379:1234–44.CrossRefPubMedGoogle Scholar
  2. 2.
    Busch K, Keller T, Fuchs U, et al. Identification of two distinct MYC breakpoint clusters and their association with various IGH breakpoint regions in the t (8; 14) translocations in sporadic Burkitt-lymphoma. Leukemia. 2007;21:1739–51.CrossRefPubMedGoogle Scholar
  3. 3.
    Kanda K, Hu H-M, Zhang L, Grandchamps J, Boxer LM. NF-κB activity is required for the deregulation of c-myc expression by the immunoglobulin heavy chain enhancer. J Biol Chem. 2000;275:32338–46.CrossRefGoogle Scholar
  4. 4.
    Karin M. Nuclear factor-κB in cancer development and progression. Nature. 2006;441(7092):431–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–45.CrossRefPubMedGoogle Scholar
  6. 6.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.CrossRefPubMedGoogle Scholar
  7. 7.
    Garkavtsev I, Kozin SV, Chernova O, et al. The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature. 2004;428:328–32.CrossRefPubMedGoogle Scholar
  8. 8.
    Alkalay I, Yaron A, Hatzubai A, Orian A, Ciechanover A, Ben-Neriah Y. Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway. Proc Natl Acad Sci. 1995;92:10599–603.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Yamaguchi K, Shirakabe K, Shibuya H, et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-β signal transduction. Science. 1995;270:2008–11.CrossRefPubMedGoogle Scholar
  10. 10.
    Chen Z, Bhoj V, Seth R. Ubiquitin, TAK1 and IKK: is there a connection? Cell Death Differ. 2006;13:687–92.CrossRefPubMedGoogle Scholar
  11. 11.
    Hayden MS, Ghosh S. Shared principles in NF-κB signaling. Cell. 2008;132:344–62.CrossRefPubMedGoogle Scholar
  12. 12.
    San Miguel J, Blade J, Boccadoro M, et al. A practical update on the use of bortezomib in the management of multiple myeloma. Oncologist. 2006;11:51–61.CrossRefPubMedGoogle Scholar
  13. 13.
    Cavo M. Proteasome inhibitor bortezomib for the treatment of multiple myeloma. Leukemia. 2006;20:1341–52.CrossRefPubMedGoogle Scholar
  14. 14.
    Chou T-C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58:621–81.CrossRefPubMedGoogle Scholar
  15. 15.
    Buglio D, Palakurthi S, Byth K, et al. Essential role of TAK1 in regulating mantle cell lymphoma survival. Blood. 2012;120:347–55.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Perkins AS, Friedberg JW. Burkitt lymphoma in adults. ASH Educ Program Book. 2008;2008:341–8.Google Scholar
  17. 17.
    Yustein JT, Dang CV. Biology and treatment of Burkitt's lymphoma. Curr Opin Hematol. 2007;14:375–81.CrossRefPubMedGoogle Scholar
  18. 18.
    Gerecitano J, Straus DJ. Treatment of Burkitt lymphoma in adults. Expert Rev Anticancer Ther. 2006;6:373–81.CrossRefPubMedGoogle Scholar
  19. 19.
    Yang X, Li X, Chen Y, et al. Apoptosis of Burkitt’s lymphoma Raji cell line induced by bortezomib. Zhongguo shi yan xue ye xue za zhi/Zhongguo bing li sheng li xue hui = J Exp Hematol/Chinese Ass Pathophysiol. 2009;17:592–6.Google Scholar
  20. 20.
    Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB. J Clin Investig. 2001;107:241.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Spencer E, Jiang J, Chen ZJ. Signal-induced ubiquitination of IκBα by the F-box protein Slimb/β-TrCP. Genes Dev. 1999;13:284–94.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Melisi D, Xia Q, Paradiso G, et al. Modulation of pancreatic cancer chemoresistance by inhibition of TAK1. J Natl Cancer Inst. 2011;103:1190–204.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Martin S, Wu Z-H, Gehlhaus K, et al. RNAi screening identifies TAK1 as a potential target for the enhanced efficacy of topoisomerase inhibitors. Curr Cancer Drug Targets. 2011;11:976.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Singh A, Sweeney MF, Yu M, et al. TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers. Cell. 2012;148:639–50.CrossRefPubMedCentralGoogle Scholar
  25. 25.
    Ahmed N, Zeng M, Sinha I, et al. The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation. Nat Immunol. 2011;12:1176–83.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Fan Y, Cheng J, Vasudevan SA, et al. TAK1 inhibitor 5Z-7-oxozeaenol sensitizes neuroblastoma to chemotherapy. Apoptosis. 2013;18:1224–34.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ale A, Bruna J, Navarro X, Udina E. Neurotoxicity induced by antineoplastic proteasome inhibitors. Neurotoxicology. 2014;43:28–35.CrossRefPubMedGoogle Scholar
  28. 28.
    Argyriou AA, Iconomou G, Kalofonos HP. Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood. 2008;112:1593–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Grosicki S, Barchnicka A, Jurczyszyn A, Grosicka A. Bortezomib for the treatment of multiple myeloma. Expert Rev Hematol. 2014;7(2):173–85.CrossRefPubMedGoogle Scholar
  30. 30.
    Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24:3113–20.CrossRefPubMedGoogle Scholar
  31. 31.
    Palumbo A, Bringhen S, Larocca A, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014;32:634–40.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Jie Zhang
    • 1
    • 2
    • 3
  • Bing Li
    • 1
  • Haixia Wu
    • 1
  • Jiayao Ou
    • 4
  • Rongbin Wei
    • 4
  • Junjun Liu
    • 4
  • Wenping Cai
    • 4
  • Xiaodong Liu
    • 5
  • Shouliang Zhao
    • 3
  • Jianhua Yang
    • 4
  • Lili Zhou
    • 1
  • Shangfeng Liu
    • 3
  • Aibin Liang
    • 1
  1. 1.Department of HematologyTongji Hospital, Tongji University School of MedicineShanghaiChina
  2. 2.College of life sciencesGuizhou UniversityGuiyangChina
  3. 3.Department of StomatologyHuashan Hospital, Fudan UniversityShanghaiChina
  4. 4.Department of OphthalmologyShanghai Tenth People’s Hospital, Tongji University School of MedicineShanghaiChina
  5. 5.Department of NeurosurgeryHuashan Hospital, Fudan UniversityShanghaiChina

Personalised recommendations