Skip to main content
SpringerLink
Log in

Melittin radiosensitizes esophageal squamous cell carcinoma with induction of apoptosis in vitro and in vivo

  • Research Article
  • Published:
Tumor Biology

Abstract

Currently, unresectable esophageal squamous cell carcinoma (ESCC) is primarily treated by chemoradiotherapy. However, the outcome has not improved significantly because of radioresistance of cancer cells. This study aimed to determine the radiosensitizing effect of melittin, a novel component of bee venom, in ESCC. ESCC cell lines were irradiated with or without melittin. Cell proliferation was detected by Cell Counting Kit 8 assay. Radiosensitization was evaluated by clonogenic survival assay. Cell apoptosis was detected by flow cytometry. Results show that melittin potently sensitized ESCC cells to radiation with a sensitization enhancement ratio of 1.15–1.42. Radiosensitization was accompanied with enhanced apoptosis and regulated by apoptosis proteins. The results were confirmed by in vivo studies on tumor-bearing xenografts. In summary, these results provide support that melittin may be a potentially promising radiosensitizer in ESCC radiation therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Reference

  1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Chen W, Zheng R, Zhang S, et al. Annual report on status of cancer in China, 2010. Chin J Cancer Res. 2014;26:48–58.

    PubMed Central  PubMed  Google Scholar 

  3. Chen W, He Y, Zheng R, et al. Esophageal cancer incidence and mortality in China, 2009. J Thorac Dis. 2013;5:19–26.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Shoji M, Ninomiya I, Makino I, et al. Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity in esophageal squamous cell carcinoma. Int J Oncol. 2012;40:2140–6.

    CAS  PubMed  Google Scholar 

  5. Huang C, Jin H, Qian Y, et al. Hybrid melittin cytolytic Peptide-driven ultrasmall lipid nanoparticles block melanoma growth in vivo. ACS Nano. 2013;7:5791–800.

    Article  CAS  PubMed  Google Scholar 

  6. Wooddell CI, Rozema DB, Hossbach M, et al. Hepatocyte-targeted RNAi therapeutics for the treatment of chronic hepatitis B virus infection. Mol Ther. 2013;21:973–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Liu H, Han Y, Fu H, et al. Construction and expression of sTRAIL-melittin combining enhanced anticancer activity with antibacterial activity in Escherichia coli. Appl Microbiol Biotechnol. 2013;97:877–2884.

    Google Scholar 

  8. Park JH, Kim KH, Lee WR, et al. Protective effect of melittin on inflammation and apoptosis in acute liver failure. Apoptosis. 2012;17:61–9.

    Article  CAS  PubMed  Google Scholar 

  9. Liu M, Zong J, Liu Z, et al. A novel melittin-MhIL-2 fusion protein inhibits the growth of human ovarian cancer SKOV3 cells in vitro and in vivo tumor growth. Cancer Immunol Immunother. 2013;62:889–95.

    Article  CAS  PubMed  Google Scholar 

  10. Rim DS, Altschuld RA, Ganote CE. Effects of calcium depletion and loading on injury during metabolic inhibition of isolated adult rat myocytes. J Mol Cell Cardiol. 1990;22:227–37.

    Article  CAS  PubMed  Google Scholar 

  11. Jo M, Park MH, Kollipara PS, et al. Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway. Toxicol Appl Pharmacol. 2012;258:72–81.

    Article  CAS  PubMed  Google Scholar 

  12. Muller UR. Hymenoptera venom proteins and peptides for diagnosis and treatment of venom allergic patients. Inflamm Allergy Drug Targets. 2011;10:420–8.

    Article  CAS  PubMed  Google Scholar 

  13. Saugar JM, Rodriguez-Hernandez MJ, de la Torre BG, et al. Activity of cecropin A-melittin hybrid peptides against colistin-resistant clinical strains of Acinetobacter baumannii: molecular basis for the differential mechanisms of action. Antimicrob Agents Chemother. 2006;50:1251–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Binder M, Fierlbeck G, King T, et al. Individual hymenoptera venom compounds induce upregulation of the basophil activation marker ectonucleotide pyrophosphatase/phosphodiesterase 3 (CD203c) in sensitized patients. Int Arch Allergy Immunol. 2002;129:160–8.

    Article  CAS  PubMed  Google Scholar 

  15. Jeong YJ, Choi Y, Shin JM et al. Melittin suppresses EGF-induced cell motility and invasion by inhibiting PI3K/Akt/mTOR signaling pathway in breast cancer cells. Food Chem Toxicol 2014.

  16. Gajski G, Garaj-Vrhovac V. Melittin: a lytic peptide with anticancer properties. Environ Toxicol Pharmacol. 2013;36:697–705.

    Article  CAS  PubMed  Google Scholar 

  17. Glinka EM. Eukaryotic expression vectors bearing genes encoding cytotoxic proteins for cancer gene therapy. Plasmid. 2012;68:69–85.

    Article  CAS  PubMed  Google Scholar 

  18. Park MH, Choi MS, Kwak DH, et al. Anti-cancer effect of bee venom in prostate cancer cells through activation of caspase pathway via inactivation of NF-kappaB. Prostate. 2011;71:801–12.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang HP, Takayama K, Su B, et al. Effect of sunitinib combined with ionizing radiation on endothelial cells. J Radiat Res. 2011;52:1–8.

    Article  PubMed  Google Scholar 

  20. Efimova EV, Liang H, Pitroda SP, et al. Radioresistance of Stat1 over-expressing tumour cells is associated with suppressed apoptotic response to cytotoxic agents and increased IL6-IL8 signalling. Int J Radiat Biol. 2009;85:421–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Wang C, Chen T, Zhang N, et al. Melittin, a major component of bee venom, sensitizes human hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating CaMKII-TAK1-JNK/p38 and inhibiting IkappaBalpha kinase-NFkappaB. J Biol Chem. 2009;284:3804–13.

    Article  CAS  PubMed  Google Scholar 

  22. Kim SJ, Park JH, Kim KH, et al. Melittin inhibits atherosclerosis in LPS/high-fat treated mice through atheroprotective actions. J Atheroscler Thromb. 2011;18:1117–26.

    Article  CAS  PubMed  Google Scholar 

  23. Kim SK, Park KY, Yoon WC, et al. Melittin enhances apoptosis through suppression of IL-6/sIL-6R complex-induced NF-kappaB and STAT3 activation and Bcl-2 expression for human fibroblast-like synoviocytes in rheumatoid arthritis. Joint Bone Spine. 2011;78:471–7.

    Article  CAS  PubMed  Google Scholar 

  24. Ezekwudo D, Shashidharamurthy R, Devineni D, et al. Inhibition of expression of anti-apoptotic protein Bcl-2 and induction of cell death in radioresistant human prostate adenocarcinoma cell line (PC-3) by methyl jasmonate. Cancer Lett. 2008;270:277–85.

    Article  CAS  PubMed  Google Scholar 

  25. Basu A, Haldar S. The relationship between BcI2, Bax and p53: consequences for cell cycle progression and cell death. Mol Hum Reprod. 1998;4:1099–109.

    Article  CAS  PubMed  Google Scholar 

  26. Jiang H, Zhao PJ, Su D et al. Paris saponin I induces apoptosis via increasing the Bax/Bcl2 ratio and caspase3 expression in gefitinibresistant nonsmall cell lung cancer in vitro and in vivo. Mol Med Rep 2014.

Download references

Acknowledgments

This work was supported by the Natural Science Foundation of China (no. 81272504), Research and Innovation Project for College Graduates of Jiangsu Province (no. CXZZ12_0588), Innovation Team (no. LJ201123 (EH11)), A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD; JX10231801), grants from Key Academic Discipline of Jiangsu Province “Medical Aspects of Specific Environments,” Six Major Talent Peak Project of Jiangsu Province (2013-WSN-040), Jiangsu Provincial Science and Technology Projects (BK2011854 (DA11)), and “333” Project of Jiangsu Province (BRA2012210 (RS12)).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guanzhou Road, Nanjing, 210029, China

    Hongcheng Zhu, Xi Yang, Jia Liu, Qin Qin, Jing Lu, Liangliang Zhan, Zheming Liu, Hao Zhang, Xiaochen Chen, Chi Zhang, Liping Xu & Xinchen Sun

  2. Department of Radiation Oncology, Nantong Tumor Hospital, Nantong, 226361, China

    Yangyang Ge

  3. Department of General Internal Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Hongyan Cheng

Authors
  1. Hongcheng Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xi Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yangyang Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qin Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jing Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Liangliang Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zheming Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaochen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Liping Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hongyan Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xinchen Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xinchen Sun.

Additional information

Hongcheng Zhu, Xi Yang, and Jia Liu contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, H., Yang, X., Liu, J. et al. Melittin radiosensitizes esophageal squamous cell carcinoma with induction of apoptosis in vitro and in vivo. Tumor Biol. 35, 8699–8705 (2014). https://doi.org/10.1007/s13277-014-2146-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2146-z

Keywords

Search

Navigation