Anti-Tumor Effects of Melittin and Its Potential Applications in Clinic

Author(s): Can Lyu, Fanfu Fang, Bai Li*.

Journal Name: Current Protein & Peptide Science

Volume 20 , Issue 3 , 2019

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Melittin, a major component of bee venom, is a water-soluble toxic peptide of which a various biological effects have been identified to be useful in anti-tumor therapy. In addition, Melittin also has anti-parasitic, anti-bacterial, anti-viral, and anti-inflammatory activities. Therefore, it is a very attractive therapeutic candidate for human diseases. However, melittin induces extensive hemolysis, a severe side effect that dampens its future development and clinical application. Thus, studies of melittin derivatives and new drug delivery systems have been conducted to explore approaches for optimizing the efficacy of this compound, while reducing its toxicity. A number of reviews have focused on each side, respectively. In this review, we summarize the research progress on the anti-tumor effects of melittin and its derivatives, and discuss its future potential clinical applications.

Keywords: Melittin, bee venom, melittin derivatives, anti-tumor effect, hemolysis, clinical applications.

Wilson, M.K.; Karakasis, K.; Oza, A.M. Outcomes and endpoints in trials of cancer treatment: The past, present, and future. Lancet Oncol., 2015, 16(1), e32-e42.
Qiu, J. ‘Back to the future’ for Chinese herbal medicines. Nat. Rev. Drug Discov., 2007, 6(7), 506-507.
Zhang, Y.H.; Wang, Y.; Yusufali, A.H.; Ashby, F.; Zhang, D.; Yin, Z.F.; Aslanidi, G.V.; Srivastava, A.; Ling, C.Q.; Ling, C. Cytotoxic genes from traditional Chinese medicine inhibit tumor growth both in vitro and in vivo. J. Integr. Med., 2014, 12(6), 483-494.
Ling, C.Q.; Yue, X.Q.; Ling, C. Three advantages of using traditional Chinese medicine to prevent and treat tumor. J. Integr. Med., 2014, 12(4), 331-335.
Lim, S.M.; Lee, S.H. Effectiveness of bee venom acupuncture in alleviating post-stroke shoulder pain: A systematic review and meta-analysis. J. Integr. Med., 2015, 13(4), 241-247.
Han, S.M.; Lee, K.G.; Pak, S.C. Effects of cosmetics containing purified honeybee (Apismellifera L.) venom on acne vulgaris. J. Integr. Med., 2013, 11(5), 320-326.
Havas, L.J. Effect of bee venom on colchicine-induced tumours. Nature, 1950, 166(4222), 567-568.
McDonald, J.A.; Li, F.P.; Mehta, C.R. Cancer mortality among beekeepers. J. Occup. Med., 1979, 21(12), 811-813.
Habermann, E. Bee and wasp venoms. Science, 1972, 177(4046), 314-322.
Kikuchi, Y.; Miyauchi, M.; Nagata, I. Inhibition of human ovarian cancer cell proliferation by calmodulin inhibitors and the possible mechanism. Gynecol. Oncol., 1989, 35(2), 156-158.
Gajski, G.; Garaj-Vrhovac, V. Melittin: A lytic peptide with anticancer properties. Environ. Toxicol. Pharmacol., 2013, 36(2), 697-705.
Orsolic, N. Bee venom in cancer therapy. Cancer Metastasis Rev., 2012, 31(1-2), 173-194.
Radloff, S.E.; Hepburn, C.; Hepburn, H.R.; Fuchs, S.; Hadisoesilo, S.; Tan, K.; Engel, M.S.; Kuznetsov, V. Population structure and classification of Apis cerana. Apidologie, 2010, 41(6), 589-601.
Park, D.; Jung, J.W.; Lee, M.O.; Lee, S.Y.; Kim, B.; Jin, H.J.; Kim, J.; Ahn, Y.J.; Lee, K.W.; Song, Y.S.; Hong, S.; Womack, J.E.; Kwon, H.W. Functional characterization of naturally occurring melittin peptide isoforms in two honey bee species, Apis mellifera and Apis cerana. Peptides, 2014, 53, 185-193.
Raghuraman, H.; Chattopadhyay, A. Melittin: A membrane-active peptide with diverse functions. Biosci. Rep., 2007, 27(4-5), 189-223.
Son, D.J.; Lee, J.W.; Lee, Y.H.; Song, H.S.; Lee, C.K.; Hong, J.T. Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds. Pharmacol. Ther., 2007, 115(2), 246-270.
Hait, W.N.; Grais, L.; Benz, C.; Cadman, E.C. Inhibition of growth of leukemic cells by inhibitors of calmodulin: Phenothiazines and melittin. Cancer Chemother. Pharmacol., 1985, 14(3), 202-205.
Saini, S.S.; Chopra, A.K.; Peterson, J.W. Melittin activates endogenous phospholipase D during cytolysis of human monocytic leukemia cells. Toxicon, 1999, 37(11), 1605-1619.
Moon, D.O.; Park, S.Y.; Choi, Y.H.; Kim, N.D.; Lee, C.; Kim, G.Y. Melittin induces Bcl-2 and caspase-3-dependent apoptosis through downregulation of Akt phosphorylation in human leukemic U937 cells. Toxicon, 2008, 51(1), 112-120.
Park, J.H.; Jeong, Y.J.; Park, K.K.; Cho, H.J.; Chung, I.K.; Min, K.S.; Kim, M.; Lee, K.G.; Yeo, J.H.; Park, K.K.; Chang, Y.C. Melittin suppresses PMA-induced tumor cell invasion by inhibiting NF-kappaB and AP-1-dependent MMP-9 expression. Mol. Cells, 2010, 29(2), 209-215.
Park, M.H.; Choi, M.S.; Kwak, D.H.; Oh, K.W. Yoon do, Y.; Han, S.B.; Song, H.S.; Song, M.J.; Hong, J.T. Anti-cancer effect of bee venom in prostate cancer cells through activation of caspase pathway via inactivation of NF-kappaB. Prostate, 2011, 71(8), 801-812.
Kikuchi, Y.; Iwano, I.; Kato, K. Effects of calmodulin antagonists on human ovarian cancer cell proliferation in vitro. Biochem. Biophys. Res. Commun., 1984, 123(1), 385-392.
Jo, M.; Park, M.H.; Kollipara, P.S.; An, B.J.; Song, H.S.; Han, S.B.; Kim, J.H.; Song, M.J.; Hong, J.T. 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(1), 72-81.
Shin, J.M.; Jeong, Y.J.; Cho, H.J.; Park, K.K.; Chung, I.K.; Lee, I.K.; Kwak, J.Y.; Chang, H.W.; Kim, C.H.; Moon, S.K.; Kim, W.J.; Choi, Y.H.; Chang, Y.C. Melittin suppresses HIF-1alpha/VEGF expression through inhibition of ERK and mTOR/p70S6K pathway in human cervical carcinoma cells. PLoS One, 2013, 8(7), e69380.
Jeong, Y.J.; Choi, Y.; Shin, J.M.; Cho, H.J.; Kang, J.H.; Park, K.K.; Choe, J.Y.; Bae, Y.S.; Han, S.M.; Kim, C.H.; Chang, H.W.; Chang, Y.C. Melittin suppresses EGF-induced cell motility and invasion by inhibiting PI3K/Akt/mTOR signaling pathway in breast cancer cells. Food Chem. Toxicol., 2014, 68, 218-225.
Cho, H.J.; Jeong, Y.J.; Park, K.K.; Park, Y.Y.; Chung, I.K.; Lee, K.G.; Yeo, J.H.; Han, S.M.; Bae, Y.S.; Chang, Y.C. Bee venom suppresses PMA-mediated MMP-9 gene activation via JNK/p38 and NF-kappaB-dependent mechanisms. J. Ethnopharmacol., 2010, 127(3), 662-668.
Lee, G.L.; Hait, W.N. Inhibition of growth of C6 astrocytoma cells by inhibitors of calmodulin. Life Sci., 1985, 36(4), 347-354.
Yang, Z.L.; Ke, Y.Q.; Xu, R.X.; Peng, P. Melittin inhibits proliferation and induces apoptosis of malignant human glioma cells. Nan Fang Yi Ke Da Xue Xue Bao, 2007, 27(11), 1775-1777.
Drechsler, S.; Andra, J. Online monitoring of metabolism and morphology of peptide-treated neuroblastoma cancer cells and keratinocytes. J. Bioenerg. Biomembr., 2011, 43(3), 275-285.
Yang, X.; Zhu, H.; Ge, Y.; Liu, J.; Cai, J.; Qin, Q.; Zhan, L.; Zhang, C.; Xu, L.; Liu, Z.; Yang, Y.; Yang, Y.; Ma, J.; Cheng, H.; Sun, X. Melittin enhances radiosensitivity of hypoxic head and neck squamous cell carcinoma by suppressing HIF-1alpha. Tumour Biol., 2014, 35(10), 10443-10448.
Zhu, H.G.; Tayeh, I.; Israel, L.; Castagna, M. Different susceptibility of lung cell lines to inhibitors of tumor promotion and inducers of differentiation. J. Biol. Regul. Homeost. Agents, 1991, 5(2), 52-58.
Chen, Y.Q.; Zhu, Z.A.; Hao, Y.Q.; Dai, K.R.; Zhang, C. Effect of melittin on apoptosis and necrosis of U2 OS cells. Zhong Xi Yi Jie He Xue Bao, 2004, 2(3), 208-209.
Chu, S.T.; Cheng, H.H.; Huang, C.J.; Chang, H.C.; Chi, C.C.; Su, H.H.; Hsu, S.S.; Wang, J.L.; Chen, I.S.; Liu, S.I.; Lu, Y.C.; Huang, J.K.; Ho, C.M.; Jan, C.R. Phospholipase A2-independent Ca2+ entry and subsequent apoptosis induced by melittin in human MG63 osteosarcoma cells. Life Sci., 2007, 80(4), 364-369.
Zhu, H.; Yang, X.; Liu, J.; Ge, Y.; Qin, Q.; Lu, J.; Zhan, L.; Liu, Z.; Zhang, H.; Chen, X.; Zhang, C.; Xu, L.; Cheng, H.; Sun, X. Melittin radio sensitizes esophageal squamous cell carcinoma with induction of apoptosis in vitro and in vivo. Tumour Biol., 2014, 35(9), 8699-8705.
Wang, R.P.; Huang, S.R.; Zhou, J.Y.; Zou, X. Synergistic interaction between melittin and chemotherapeutic agents and their possible mechanisms: An experimental research. Zhongguo Zhong Xi Yi Jie He ZaZhi, 2014, 34(2), 224-229.
Arora, A.S.; de Groen, P.C.; Croall, D.E.; Emori, Y.; Gores, G.J. Hepatocellular carcinoma cells resist necrosis during anoxia by preventing phospholipase-mediated calpain activation. J. Cell. Physiol., 1996, 167(3), 434-442.
Zhang, H.; Zhao, B.; Huang, C.; Meng, X.M.; Bian, E.B.; Li, J. Melittin restores PTEN expression by down-regulating HDAC2 in human hepatocelluar carcinoma HepG2 cells. PLoS One, 2014, 9(5), e95520.
Li, B.; Gu, W.; Zhang, C.; Huang, X.Q.; Han, K.Q.; Ling, C.Q. Growth arrest and apoptosis of the human hepatocellular carcinoma cell line BEL-7402 induced by melittin. Onkologie, 2006, 29(8-9), 367-371.
Li, B.; Ling, C.Q.; Zhang, C.; Gu, W.; Li, S.X.; Huang, X.Q.; Zhang, Y.N.; Yu, C.Q. The induced apoptosis of recombinant adenovirus carrying melittin gene for hepatocellular carcinoma cell. Zhonghua Gan Zang Bing Za Zhi, 2004, 12(8), 453-455.
Zhang, C.; Li, B.; Lu, S.Q.; Li, Y.; Su, Y.H.; Ling, C.Q. Effects of melittin on expressions of mitochondria membrane protein 7A6, cell apoptosis-related gene products Fas and Fas ligand in hepatocarcinoma cells. Zhong Xi Yi Jie He XueBao, 2007, 5(5), 559-563.
Wang, C.; Chen, T.; Zhang, N.; Yang, M.; Li, B.; Lu, X.; Cao, X.; Ling, C. 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 I kappa B alpha kinase-NF kappa B. J. Biol. Chem., 2009, 284(6), 3804-3813.
Song, C.C.; Lu, X.; Cheng, B.B.; Du, J.; Li, B.; Ling, C.Q. Effects of melittin on growth and angiogenesis of human hepatocellular carcinoma BEL-7402 cell xenografts in nude mice. Ai Zheng, 2007, 26(12), 1315-1322.
Liu, S.; Yu, M.; He, Y.; Xiao, L.; Wang, F.; Song, C.; Sun, S.; Ling, C.; Xu, Z. Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway. Hepatology, 2008, 47(6), 1964-1973.
Tu, W.C.; Wu, C.C.; Hsieh, H.L.; Chen, C.Y.; Hsu, S.L. Honeybee venom induces calcium-dependent but caspase-independent apoptotic cell death in human melanoma A2058 cells. Toxicon, 2008, 52(2), 318-329.
Do, N.; Weindl, G.; Grohmann, L.; Salwiczek, M.; Koksch, B.; Korting, H.C.; Schafer-Korting, M. Cationic membrane-active peptides - anticancer and antifungal activity as well as penetration into human skin. Exp. Dermatol., 2014, 23(5), 326-331.
Lee, S.Y.; Park, H.S.; Lee, S.J.; Choi, M.U. Melittin exerts multiple effects on the release of free fatty acids from L1210 cells: Lack of selective activation of phospholipase A2 by melittin. Arch. Biochem. Biophys., 2001, 389(1), 57-67.
Heston, W.D.; Charles, M. Calmodulin antagonist inhibition of polyamine transport in prostatic cancer cells in vitro. Biochem. Pharmacol., 1988, 37(13), 2511-2514.
Thomas, T.; Thomas, T.J. Polyamine metabolism and cancer. J. Cell. Mol. Med., 2003, 7(2), 113-126.
Marton, L.J.; Pegg, A.E. Polyamines as targets for therapeutic intervention. Annu. Rev. Pharmacol. Toxicol., 1995, 35, 55-91.
Grillo, M.A.; Colombatto, S. Polyamine transport in cells. Biochem. Soc. Trans., 1994, 22(4), 894-898.
Wu, S.N.; Li, H.F.; Chiang, H.T. Characterization of ATP-sensitive potassium channels functionally expressed in pituitary GH3 cells. J. Membr. Biol., 2000, 178(3), 205-214.
Ryu, J.S.; Jang, B.H.; Jo, Y.S.; Kim, S.J.; Eom, T.I.; Kim, M.C.; Ko, H.J.; Sim, S.S. The effect of acteoside on intracellular Ca(2+) mobilization and phospholipase C activity in RBL-2H3 cells stimulated by melittin. Arch. Pharm. Res., 2014, 37(2), 239-244.
Yu, S.P.; Canzoniero, L.M.; Choi, D.W. Ion homeostasis and apoptosis. Curr. Opin. Cell Biol., 2001, 13(4), 405-411.
Brown, E.M.; MacLeod, R.J. Extracellular calcium sensing and extracellular calcium signaling. Physiol. Rev., 2001, 81(1), 239-297.
Gerst, J.E.; Salomon, Y. Inhibition by melittin and fluphenazine of melanotropin receptor function and adenylate cyclase in M2R melanoma cell membranes. Endocrinology, 1987, 121(5), 1766-1772.
Heisler, S. Calmodulin antagonists inhibit dihydropyridine calcium channel activator (BAY-K-8644) induced cGMP synthesis in pituitary tumor cells. Can. J. Physiol. Pharmacol., 1986, 64(6), 760-763.
Lazo, J.S.; Hait, W.N.; Kennedy, K.A.; Braun, I.D.; Meandzija, B. Enhanced bleomycin-induced DNA damage and cytotoxicity with calmodulin antagonists. Mol. Pharmacol., 1985, 27(3), 387-393.
Zimmermann, K.C.; Green, D.R. How cells die: Apoptosis pathways. J. Allergy Clin. Immunol., 2001, 108(4)(Suppl.), S99-S103.
Wajant, H. The Fas signaling pathway: More than a paradigm. Science, 2002, 296(5573), 1635-1636.
Roh, Y.S.; Song, J.; Seki, E. TAK1 regulates hepatic cell survival and carcinogenesis. J. Gastroenterol., 2014, 49(2), 185-194.
Mihaly, S.R.; Ninomiya-Tsuji, J.; Morioka, S. TAK1 control of cell death. Cell Death Differ., 2014, 21(11), 1667-1676.
Lee, J.; Lee, D.G. Melittin triggers apoptosis in Candida albicans through the reactive oxygen species-mediated mitochondria/ caspase-dependent pathway. FEMS Microbiol. Lett., 2014, 355(1), 36-42.
Bonora, M.; Pinton, P. The mitochondrial permeability transition pore and cancer: molecular mechanisms involved in cell death. Front. Oncol., 2014, 4, 302.
Nicotra, A.; Parvez, S. Apoptotic molecules and MPTP-induced cell death. Neurotoxicol. Teratol., 2002, 24(5), 599-605.
Grad, J.M.; Zeng, X.R.; Boise, L.H. Regulation of Bcl-xL: A little bit of this and a little bit of STAT. Curr. Opin. Oncol., 2000, 12(6), 543-549.
Al Zaid Siddiquee, K.; Turkson, J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res., 2008, 18(2), 254-267.
Oeckinghaus, A.; Hayden, M.S.; Ghosh, S. Crosstalk in NF-kappaB signaling pathways. Nat. Immunol., 2011, 12(8), 695-708.
Perkins, N.D. The diverse and complex roles of NF-kappa B subunits in cancer. Nat. Rev. Cancer, 2012, 12(2), 121-132.
Watala, C.; Gwozdzinski, K. Melittin-induced alterations in dynamic properties of human red blood cell membranes. Chem. Biol. Interact., 1992, 82(2), 135-149.
Blondelle, S.E.; Houghten, R.A. Hemolytic and antimicrobial activities of the twenty-four individual omission analogues of melittin. Biochemistry, 1991, 30(19), 4671-4678.
Ladokhin, A.S.; White, S.H. Folding of amphipathic alpha-helices on membranes: Energetics of helix formation by melittin. J. Mol. Biol., 1999, 285(4), 1363-1369.
Andersson, M.; Ulmschneider, J.P.; Ulmschneider, M.B.; White, S.H. Conformational states of melittin at a bilayer interface. Biophys. J., 2013, 104(6), L12-L14.
Rapson, A.C.; Hossain, M.A.; Wade, J.D.; Nice, E.C.; Smith, T.A.; Clayton, A.H.; Gee, M.L. Structural dynamics of a lytic peptide interacting with a supported lipid bilayer. Biophys. J., 2011, 100(5), 1353-1361.
Terwilliger, T.C.; Weissman, L.; Eisenberg, D. The structure of melittin in the form I crystals and its implication for melittin’s lytic and surface activities. Biophys. J., 1982, 37(1), 353-361.
Wessman, P.; Morin, M.; Reijmar, K.; Edwards, K. Effect of alpha-helical peptides on liposome structure: A comparative study of melittin and alamethicin. J. Colloid Interface Sci., 2010, 346(1), 127-135.
Lee, M.T.; Sun, T.L.; Hung, W.C.; Huang, H.W. Process of inducing pores in membranes by melittin. Proc. Natl. Acad. Sci. USA, 2013, 110(35), 14243-14248.
Hain, N.; Gallego, M.; Reviakine, I. Unraveling supported lipid bilayer formation kinetics: Osmotic effects. Langmuir, 2013, 29(7), 2282-2288.
Kokot, G.; Mally, M.; Svetina, S. The dynamics of melittin-induced membrane permeability. Eur. Biophys. J., 2012, 41(5), 461-474.
Sengupta, D.; Leontiadou, H.; Mark, A.E.; Marrink, S.J. Toroidal pores formed by antimicrobial peptides show significant disorder. Biochim. Biophys. Acta, 2008, 1778(10), 2308-2317.
Allende, D.; Simon, S.A.; McIntosh, T.J. Melittin-induced bilayer leakage depends on lipid material properties: Evidence for toroidal pores. Biophys. J., 2005, 88(3), 1828-1837.
Beven, L.; Castano, S.; Dufourcq, J.; Wieslander, A.; Wroblewski, H. The antibiotic activity of cationic linear amphipathic peptides: Lessons from the action of leucine/lysine copolymers on bacteria of the class Mollicutes. Eur. J. Biochem., 2003, 270(10), 2207-2217.
Irudayam, S.J.; Berkowitz, M.L. Influence of the arrangement and secondary structure of melittin peptides on the formation and stability of toroidal pores. Biochim. Biophys. Acta, 2011, 1808(9), 2258-2266.
Maher, S.; Devocelle, M.; Ryan, S.; McClean, S.; Brayden, D.J. Impact of amino acid replacements on in vitro permeation enhancement and cytotoxicity of the intestinal absorption promoter, melittin. Int. J. Pharm., 2010, 387(1-2), 154-160.
Mihajlovic, M.; Lazaridis, T. Antimicrobial peptides bind more strongly to membrane pores. Biochim. Biophys. Acta, 2010, 1798(8), 1494-1502.
Svensson, F.R.; Lincoln, P.; Norden, B.; Esbjorner, E.K. Tryptophan orientations in membrane-bound gramicidin and melittin-a comparative linear dichroism study on transmembrane and surface-bound peptides. Biochim. Biophys. Acta, 2011, 1808(1), 219-228.
Misra, S.K.; Ye, M.; Kim, S.; Pan, D. Defined nanoscale chemistry influences delivery of peptido-toxins for cancer therapy. PLoS One, 2015, 10(6), e0125908.
Pan, H.; Soman, N.R.; Schlesinger, P.H.; Lanza, G.M.; Wickline, S.A. Cytolytic peptide nanoparticles (‘NanoBees’) for cancer therapy. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., 2011, 3(3), 318-327.
Hou, K.K.; Pan, H.; Schlesinger, P.H.; Wickline, S.A. A role for peptides in overcoming endosomal entrapment in siRNA delivery - A focus on melittin. Biotechnol. Adv., 2015, 33(6 Pt 1), 931-940.
Dempsey, C.E. The actions of melittin on membranes. Biochim. Biophys. Acta, 1990, 1031(2), 143-161.
Otoda, K.; Kimura, S.; Imanishi, Y. Interaction of melittin derivatives with lipid bilayer membrane. Role of basic residues at the C-terminal and their replacement with lactose. Biochim. Biophys. Acta, 1992, 1112(1), 1-6.
Tan, Y.X.; Chen, C.; Wang, Y.L.; Lin, S.; Wang, Y.; Li, S.B.; Jin, X.P.; Gao, H.W.; Du, F.S.; Gong, F.; Ji, S.P. Truncated peptides from melittin and its analog with high lytic activity at endosomal pH enhance branched polyethylenimine-mediated gene transfection. J. Gene Med., 2012, 14(4), 241-250.
Yan, H.; Li, S.; Sun, X.; Mi, H.; He, B. Individual substitution analogs of Mel(12-26), melittin’s C-terminal 15-residue peptide: Their antimicrobial and hemolytic actions. FEBS Lett., 2003, 554(1-2), 100-104.
Habermann, E.; Kowallek, H. Modifications of amino groups and tryptophan in melittin as an aid to recognition of structure-activity relationships. Hoppe Seylers Z. Physiol. Chem., 1970, 351(7), 884-890.
Rivett, D.E.; Kirkpatrick, A.; Hewish, D.R.; Reilly, W.; Werkmeister, J.A. Dimerization of truncated melittin analogues results in cytolytic peptides. Biochem. J., 1996, 316(Pt 2), 525-529.
Jamasbi, E.; Batinovic, S.; Sharples, R.A.; Sani, M.A.; Robins-Browne, R.M.; Wade, J.D.; Separovic, F.; Hossain, M.A. Melittin peptides exhibit different activity on different cells and model membranes. Amino Acids, 2014, 46(12), 2759-2766.
Werkmeister, J.A.; Kirkpatrick, A.; McKenzie, J.A.; Rivett, D.E. The effect of sequence variations and structure on the cytolytic activity of melittin peptides. Biochim. Biophys. Acta, 1993, 1157(1), 50-54.
Weaver, A.J.; Kemple, M.D.; Prendergast, F.G. Characterization of selectively 13C-labeled synthetic melittin and melittin analogues in isotropic solvents by circular dichroism, fluorescence, and NMR spectroscopy. Biochemistry, 1989, 28(21), 8614-8623.
Subbalakshmi, C.; Nagaraj, R.; Sitaram, N. Biological activities of C-terminal 15-residue synthetic fragment of melittin: Design of an analog with improved antibacterial activity. FEBS Lett., 1999, 448(1), 62-66.
Asthana, N.; Yadav, S.P.; Ghosh, J.K. Dissection of antibacterial and toxic activity of melittin: A leucine zipper motif plays a crucial role in determining its hemolytic activity but not antibacterial activity. J. Biol. Chem., 2004, 279(53), 55042-55050.
Saravanan, R.; Bhunia, A.; Bhattacharjya, S. Micelle-bound structures and dynamics of the hinge deleted analog of melittin and its diastereomer: Implications in cell selective lysis by D-amino acid containing antimicrobial peptides. Biochim. Biophys. Acta, 2010, 1798(2), 128-139.
Sun, X.; Chen, S.; Li, S.; Yan, H.; Fan, Y.; Mi, H. Deletion of two C-terminal Gln residues of 12-26-residue fragment of melittin improves its antimicrobial activity. Peptides, 2005, 26(3), 369-375.
Juvvadi, P.; Vunnam, S.; Merrifield, E.L.; Boman, H.G.; Merrifield, R.B. Hydrophobic effects on antibacterial and channel-forming properties of cecropin A-melittin hybrids. J. Pept. Sci., 1996, 2(4), 223-232.
Merrifield, E.L.; Mitchell, S.A.; Ubach, J.; Boman, H.G.; Andreu, D.; Merrifield, R.B. D-enantiomers of 15-residue cecropin A-melittin hybrids. Int. J. Pept. Protein Res., 1995, 46(3-4), 214-220.
Wade, D.; Andreu, D.; Mitchell, S.A.; Silveira, A.M.; Boman, A.; Boman, H.G.; Merrifield, R.B. Antibacterial peptides designed as analogs or hybrids of cecropins and melittin. Int. J. Pept. Protein Res., 1992, 40(5), 429-436.
Huang, Y.; Liu, F.P.; Zhou, T.H.; Zhu, J.M. Cloning and expression of a synthetic gene encoding magainin-melittin hybrid peptide in Escherichia coli and studies on its antibacterial activity. Sheng Wu Gong Cheng Xue Bao, 2001, 17(2), 207-210.
Ji, S.; Li, W.; Zhang, L.; Zhang, Y.; Cao, B. Cecropin A-melittin mutant with improved proteolytic stability and enhanced antimicrobial activity against bacteria and fungi associated with gastroenteritis in vitro. Biochem. Biophys. Res. Commun., 2014, 451(4), 650-655.
Russell, P.J.; Hewish, D.; Carter, T.; Sterling-Levis, K.; Ow, K.; Hattarki, M.; Doughty, L.; Guthrie, R.; Shapira, D.; Molloy, P.L.; Werkmeister, J.A.; Kortt, A.A. Cytotoxic properties of immunoconjugates containing melittin-like peptide 101 against prostate cancer: In vitro and in vivo studies. Cancer Immunol. Immunother., 2004, 53(5), 411-421.
Liu, H.; Han, Y.; Fu, H.; Liu, M.; Wu, J.; Chen, X.; Zhang, S.; Chen, Y. Construction and expression of sTRAIL-melittin combining enhanced anticancer activity with antibacterial activity in Escherichia coli. Appl. Microbiol. Biotechnol., 2013, 97(7), 2877-2884.
Holle, L.; Song, W.; Holle, E.; Wei, Y.; Wagner, T.; Yu, X. A matrix metalloproteinase 2 cleavable melittin/avidin conjugate specifically targets tumor cells in vitro and in vivo. Int. J. Oncol., 2003, 22(1), 93-98.
Su, M.; Chang, W.; Cui, M.; Lin, Y.; Wu, S.; Xu, T. Expression and anticancer activity analysis of recombinant human uPA143-melittin. Int. J. Oncol., 2015, 46(2), 619-626.
Liu, M.; Zong, J.; Liu, Z.; Li, L.; Zheng, X.; Wang, B.; Sun, G. 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(5), 889-895.
Cui, F.; Cun, D.; Tao, A.; Yang, M.; Shi, K.; Zhao, M.; Guan, Y. Preparation and characterization of melittin-loaded poly (DL-lactic acid) or poly (DL-lactic-co-glycolic acid) microspheres made by the double emulsion method. J. Control. Release, 2005, 107(2), 310-319.
Soman, N.R.; Lanza, G.M.; Heuser, J.M.; Schlesinger, P.H.; Wickline, S.A. Synthesis and characterization of stable fluorocarbon nanostructures as drug delivery vehicles for cytolytic peptides. Nano Lett., 2008, 8(4), 1131-1136.
Huang, C.; Jin, H.; Qian, Y.; Qi, S.; Luo, H.; Luo, Q.; Zhang, Z. Hybrid melittin cytolytic Peptide-driven ultra small lipid nanoparticles block melanoma growth in vivo. ACS Nano, 2013, 7(7), 5791-5800.
Bei, C.; Bindu, T.; Remant, K.C.; Peisheng, X. Dual secured nano-melittin for the safe and effective eradication of cancer cells. J. Mater. Chem. B Mater. Biol. Med., 2015, 3(1), 25-29.
Ahmad, A.; Ranjan, S.; Zhang, W.; Zou, J.; Pyykko, I.; Kinnunen, P.K. Novel endosomolytic peptides for enhancing gene delivery in nanoparticles. Biochim. Biophys. Acta, 2015, 1848(2), 544-553.
Piyasena, M.E.; Zeineldin, R.; Fenton, K.; Buranda, T.; Lopez, G.P. Biosensors based on release of compounds upon disruption of lipid bilayers supported on porous microspheres. Biointerphases, 2008, 3(2), 38.
Buhrman, J.S.; Cook, L.C.; Rayahin, J.E.; Federle, M.J.; Gemeinhart, R.A. Proteolytically activated anti-bacterial hydrogel microspheres. J. Control. Release, 2013, 171(3), 288-295.
Tian, J.L.; Ke, X.; Chen, Z.; Wang, C.J.; Zhang, Y.; Zhong, T.C. Melittin liposomes surface modified with poloxamer 188: In vitro characterization and in vivo evaluation. Pharmazie, 2011, 66(5), 362-367.
Ling, C.Q.; Li, B.; Zhang, C.; Zhu, D.Z.; Huang, X.Q.; Gu, W.; Li, S.X. Inhibitory effect of recombinant adenovirus carrying melittin gene on hepatocellular carcinoma. Ann. Oncol., 2005, 16(1), 109-115.
Bastone, P.; Romen, F.; Liu, W.; Wirtz, R.; Koch, U.; Josephson, N.; Langbein, S.; Lochelt, M. Construction and characterization of efficient, stable and safe replication-deficient foamy virus vectors. Gene Ther., 2007, 14(7), 613-620.
McCown, T.J. The future of epilepsy treatment: focus on adeno-associated virus vector gene therapy. Drug News Perspect., 2010, 23(5), 281-286.
Yao, X.L.; Nakagawa, S.; Gao, J.Q. Current targeting strategies for adenovirus vectors in cancer gene therapy. Curr. Cancer Drug Targets, 2011, 11(7), 810-825.
Malhotra, M.; Kulamarva, A.; Sebak, S.; Paul, A.; Bhathena, J.; Mirzaei, M.; Prakash, S. Ultrafine chitosan nanoparticles as an efficient nucleic acid delivery system targeting neuronal cells. Drug Dev. Ind. Pharm., 2009, 35(6), 719-726.
Serikawa, T.; Kikuchi, A.; Sugaya, S.; Suzuki, N.; Kikuchi, H.; Tanaka, K. In vitro and in vivo evaluation of novel cationic liposomes utilized for cancer gene therapy. J. Control. Release, 2006, 113(3), 255-260.
Li, S.X.; Ling, C.Q.; Liu, X.Y. Impact of infection with recombinant adenovirus carrying melittin gene on CD54 expression in HepG2 cells. Di Yi Jun Yi Da XueXueBao, 2003, 23(4), 300-305.
Ling, C.Q.; Li, B.; Zhang, C.; Gu, W.; Li, S.X.; Huang, X.Q.; Zhang, Y.N. Anti-hepatocarcinoma effect of recombinant adenovirus carrying melittin gene. ZhonghuaGanZang Bing ZaZhi, 2004, 12(12), 741-744.
Holle, L.; Song, W.; Holle, E.; Wei, Y.; Li, J.; Wagner, T.E.; Yu, X. In vitro- and in vivo-targeted tumor lysis by an MMP2 cleavable melittin-LAP fusion protein. Int. J. Oncol., 2009, 35(4), 829-835.
Salomone, F.; Cardarelli, F.; Signore, G.; Boccardi, C.; Beltram, F. In vitro efficient transfection by CM(1)(8)-Tat(1)(1) hybrid peptide: A new tool for gene-delivery applications. PLoS One, 2013, 8(7), e70108.
Ling, C.; Wang, Y.; Zhang, Y.; Ejjigani, A.; Yin, Z.; Lu, Y.; Wang, L.; Wang, M.; Li, J.; Hu, Z.; Aslanidi, G.V.; Zhong, L.; Gao, G.; Srivastava, A.; Ling, C. Selective in vivo targeting of human liver tumors by optimized AAV3 vectors in a murine xenograft model. Hum. Gene Ther., 2014, 25(12), 1023-1034.
Soman, N.R.; Baldwin, S.L.; Hu, G.; Marsh, J.N.; Lanza, G.M.; Heuser, J.E.; Arbeit, J.M.; Wickline, S.A.; Schlesinger, P.H. Molecularly targeted nanocarriers deliver the cytolytic peptide melittin specifically to tumor cells in mice, reducing tumor growth. J. Clin. Invest., 2009, 119(9), 2830-2842.
Piscotta, F.J.; Tharp, J.M.; Liu, W.R.; Link, A.J. Expanding the chemical diversity of lasso peptide MccJ25 with genetically encoded noncanonical amino acids. Chem. Commun., 2015, 51(2), 409-412.

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Article Details

Year: 2019
Page: [240 - 250]
Pages: 11
DOI: 10.2174/1389203719666180612084615
Price: $58

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