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Published in: Tumor Biology 9/2014

01-09-2014 | Research Article

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

Authors: Hongcheng Zhu, Xi Yang, Jia Liu, Yangyang Ge, Qin Qin, Jing Lu, Liangliang Zhan, Zheming Liu, Hao Zhang, Xiaochen Chen, Chi Zhang, Liping Xu, Hongyan Cheng, Xinchen Sun

Published in: Tumor Biology | Issue 9/2014

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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.
Literature
1.
2.
4.
go back to reference 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.PubMed 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.PubMed
5.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
6.
go back to reference 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed
7.
go back to reference 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. 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.
8.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
9.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
10.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
11.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
12.
go back to reference Muller UR. Hymenoptera venom proteins and peptides for diagnosis and treatment of venom allergic patients. Inflamm Allergy Drug Targets. 2011;10:420–8.CrossRefPubMed Muller UR. Hymenoptera venom proteins and peptides for diagnosis and treatment of venom allergic patients. Inflamm Allergy Drug Targets. 2011;10:420–8.CrossRefPubMed
13.
go back to reference 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed
14.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
15.
go back to reference 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. 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.
go back to reference Gajski G, Garaj-Vrhovac V. Melittin: a lytic peptide with anticancer properties. Environ Toxicol Pharmacol. 2013;36:697–705.CrossRefPubMed Gajski G, Garaj-Vrhovac V. Melittin: a lytic peptide with anticancer properties. Environ Toxicol Pharmacol. 2013;36:697–705.CrossRefPubMed
17.
go back to reference Glinka EM. Eukaryotic expression vectors bearing genes encoding cytotoxic proteins for cancer gene therapy. Plasmid. 2012;68:69–85.CrossRefPubMed Glinka EM. Eukaryotic expression vectors bearing genes encoding cytotoxic proteins for cancer gene therapy. Plasmid. 2012;68:69–85.CrossRefPubMed
18.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
19.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
20.
go back to reference 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.PubMedCentralCrossRefPubMed 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.PubMedCentralCrossRefPubMed
21.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
22.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
23.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
24.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
25.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
26.
go back to reference 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. 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.
Metadata
Title
Melittin radiosensitizes esophageal squamous cell carcinoma with induction of apoptosis in vitro and in vivo
Authors
Hongcheng Zhu
Xi Yang
Jia Liu
Yangyang Ge
Qin Qin
Jing Lu
Liangliang Zhan
Zheming Liu
Hao Zhang
Xiaochen Chen
Chi Zhang
Liping Xu
Hongyan Cheng
Xinchen Sun
Publication date
01-09-2014
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 9/2014
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-014-2146-z

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