A conjugate of the lytic peptide Hecate and gallic acid: structure, activity against cervical cancer, and toxicity
Tóm tắt
Conjugate compounds constitute a new class of molecules
of important biological interest mainly for the treatment of diseases such as cancer. The N-terminus region of cationic peptides has been described as important for their biological activity. The aim of this study was to evaluate the lytic peptide Hecate (FALALKALKKALKKLKKALKKAL) and the effect of conjugating this macromolecule with gallic acid (C7H6O5) in terms of structure, anti-cancer activity, and toxicity. An N-terminus GA-Hecate peptide conjugate was synthesized to provide information regarding the relationship between the amino-terminal region and its charge and the secondary structure and biological activity of the peptide; and the effects of gallic acid on these parameters. Peptide secondary structure was confirmed using circular dichroism (CD). The CD measurements showed that the peptide has a high incidence of α-helical structures in the presence of SDS and LPC, while GA-Hecate presented lower incidence of α-helical structures in the same chemical environment. An evaluation of the anti-cancer activity in HeLa cancer cells indicated that both peptides are active, but that coupling gallic acid at the N-terminus decreased the activity of the free peptide. GA-Hecate showed lower activity in non-tumor keratinocyte cells but higher hemolytic activity. Our findings suggest that the N-terminus of Hecate plays an important role in its activity against cervical cancer by affecting it secondary structure, toxicity, and hemolytic activity. This study highlights the importance of the N-terminus in antitumor activity and could provide an important tool for developing new anti-cancer drugs.
Tài liệu tham khảo
Aruoma OI, Murcia A, Butler J, Halliwell B (1993) Valuation of antioxidant and prooxidant actions of gallic acid and its derivatives. J Agric Food Chem 41:1880–1885
Asnaashari M, Farhoosh R, Sharif A (2014) Antioxidant activity of gallic acid and methyl gallate in triacylglycerols of Kilka fish oil and its oil-in-water emulsion. Food Chem 159:439–444. doi:10.1016/j.foodchem.2014.03.038
Baranska-Rybak W, Pikula M, Dawgul M, Kamysz W, Trzonkowski P, Roszkiewicz J (2013) Safety profile of antimicrobial peptides: camel, citropin, protegrin, temporin A and lipopeptide on HaCaT keratinocytes. Acta Pol Pharm 70:795–801
Barr SC, Rose D, Jaynes JM (1995) Activity of lytic peptides against intracellular Trypanosoma cruzi amastigotes in vitro and parasitemias in mice. J Parasitol 81:974–978
Barrajón-Catalán E, Menéndez-Gutiérrez MP, Falco A et al (2010) Selective death of human breast cancer cells by lytic immunoliposomes: correlation with their HER2 expression level. Cancer Lett 290:192–203. doi:10.1016/j.canlet.2009.09.010
Batista MN, Carneiro BM, Braga ACS, Rahal P (2014) Caffeine inhibits hepatitis C virus replication in vitro. Arch Virol. doi:10.1007/s00705-014-2302-1
Bernhaus A, Fritzer-Szekeres M, Grusch M et al (2009) Digalloylresveratrol, a new phenolic acid derivative induces apoptosis and cell cycle arrest in human HT-29 colon cancer cells. Cancer Lett 274:299–304. doi:10.1016/j.canlet.2008.09.020
Bodek G, Kowalczyk A, Waclawik A et al (2005) Targeted ablation of prostate carcinoma cells through LH receptor using hecate-CGβ conjugate: functional characteristic and molecular mechanism of cell death pathway. Exp Biol Med 230:421–428
Buolamwini JK (1999) Novel anticancer drug discovery. Curr Opin Chem Biol 3:500–509
Castro MS, Cilli EM, Fontes W (2006) Combinatorial synthesis and directed evolution applied to the production of α-helix forming antimicrobial peptides analogues. Curr Protein Pep Sci 7:473–478
Cespedes GF, Lorenzon EN, Vicente EF, Soares Mendes-Giannini MJ, Fontes W, Castro MS, Cilli EM (2012) Mechanism of action and relationship between structure and biological activity of Ctx-Ha: a new ceratotoxin-like peptide from Hypsiboas albopunctatus. Protein Pept Lett 19:596–603
Cilli EM, Pigossi FT, Crusca E et al (2007) Correlations between differences in amino-terminal sequences and different hemolytic activity of sticholysins. Toxicon 50:1201–1204. doi:10.1016/j.toxicon.2007.07.013
Cordova CAS, Locatelli C, Assunção LS et al (2011) Octyl and dodecyl gallates induce oxidative stress and apoptosis in a melanoma cell line. Toxicol Vitr 25:2025–2034. doi:10.1016/j.tiv.2011.08.003
Crusca E, Rezende AA, Marchetto R et al (2011) Influence of N-terminal modifications on the biological activity, membrane interaction, and secondary structure of the antimicrobial peptide hylin-a1. Biopolymers 96:41–48. doi:10.1002/bip.21454
Dathe M, Wieprecht T, Nikolenko H, Handel L, Maloy WL, MacDonald DL, Beyermann M, Bienert M (1997) Hydrophobicity, hydrophobic moment and angle subtended by charged residues modulate antibacterial and hemolytic activity of amphipathic helical peptides. FEBS Lett 403:208–212
Duncan R (2006) Polymer conjugates as anticancer nanomedicines. Nat Rev Cancer 6:688–701. doi:10.1038/nrc1958
Duval E, Zatylny C, Laurencin M, Baudy-Floc’h M, Henry J (2009) KKKKPLFGLFFGLF: a cationic peptide designed to exert antibacterial activity. Peptides 30:1608–1612
Eisenberg D, Weiss RM, Terwilliger TC (1984) The hydrophobic moment detects periodicity in protein hydrophobicity. Proc Natl Acad Sci USA 81:140–144
Ferlay J, Shin H-R, Bray F et al (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917
Fjell CD, Hiss JA, Hancock REW, Schneider G (2011) Designing antimicrobial peptides: form follows function. Nat Rev Drug Discov. doi:10.1038/nrd3591
Gao X, Zhang X, Wang Y, Peng S, Fan C (2015) An in vitro study on the cytotoxicity of bismuth oxychloride nanosheets in human HaCaT keratinocytes. Food Chem Toxicol 80:52–61. doi:10.1016/j.fct.2015.02.018
Gaspar D, Veiga AS, Castanho MARB (2013) From antimicrobial to anticancer peptides: a review. Front Microbiol. doi:10.3389/fmicb.2013.00294
Gawronska B, Leuschner C, Enrigh F, Hansel W (2002) Effects of a lytic peptide conjugated to β hCG on ovarian cancer: studies in vitro and in vivo. Gynecol Oncol 85:45–52
Golubeva OY, Shamova OV, Orlov DS et al (2011) Synthesis and study of antimicrobial activity of bioconjugates of silver nanoparticles and endogenous antibiotics. Glass Phys Chem 37:78–84. doi:10.1134/S1087659611010056
Hansel W, Leuschner C, Gawronska B, Enright F (2001) Targeted destruction of prostate cancer cells and xenografts by lytic peptide-betaLH conjugates. Reprod Biol 1:20–32
Hansel W, Enright F, Leuschner C (2007a) Destruction of breast cancers and their metastases by lytic peptide conjugates in vitro and in vivo. Mol Cell Endocrinol 260–262:183–189. doi:10.1016/j.mce.2005.12.056
Hansel W, Leuschner C, Enright F (2007b) Conjugates of lytic peptides and LHRH or βCG target and cause necrosis of prostate cancers and metastases. Mol Cell Endocrinol 269:26–33
Henk WG, Todd WJ, Enright FM, Mitchell PS (1995) The morphological effects of two antimicrobial peptides, hecate-1 and melittin, on Escherichia coli. Scan Microsc 9:501–507
Hirata A, Nokihara K (2014) Construction of peptide-vehicles, bioconjugates having modules for cancer cell surface capture and cell-penetrating peptide with anticancer agents. Tetrahedron Lett 55:4091–4094. doi:10.1016/j.tetlet.2014.05.086
Ho H-H, Chang C-S, Ho W-C et al (2013) Gallic acid inhibits gastric cancer cells metastasis and invasive growth via increased expression of RhoB, downregulation of AKT/small GTPase signals and inhibition of NF-κB activity. Toxicol Appl Pharmacol 266:76–85. doi:10.1016/j.taap.2012.10.019
Howl J (2005) Peptide synthesis and applications, vol 31. Humana Press, Totowa
Huang Y, Wang X, Wang H et al (2011) Studies on mechanism of action of anticancer peptides by modulation of hydrophobicity within a defined structural framework. Mol Cancer Ther 10:416–426. doi:10.1158/1535-7163.mct-10-0811
Hudecz F (2005) Synthesis of peptide bioconjugates. Methods Mol Biol 298:209–223
Hurtado C, Bustos MJ, Sabina P, Nogal ML, Granja AG, González ME, Gónzalez-Porqué P, Revilla Y, Carrascosa AL (2008) Antiviral activity of lauryl gallate against animal viruses. Antvir Ther 13:909–917
Jamasbi E, Batinovic S, Sharples RA, Sani M-A, Robins-Browne RM, Wade JD, Separovic F, Hossain MA (2014) Melittin peptides exhibit different activity on different cells and model membranes. Amino Acids 46:2759–2766
Kee HJ, Cho S-N, Kim GR et al (2014) Gallic acid inhibits vascular calcification through the blockade of BMP2–Smad1/5/8 signaling pathway. Vasc Pharmacol 63:71–78. doi:10.1016/j.vph.2014.08.005
Kitagawa S, Nabekura T, Kamiyama S et al (2005) Effects of alkyl gallates on P-glycoprotein function. Biochem Pharmacol 70:1262–1266. doi:10.1016/j.bcp.2005.07.013
Ko T-C, Hour M-J, Lien J-C et al (2001) Synthesis of 4-alkoxy-2-phenylquinoline derivatives as potent antiplatelet agents. Bioorg Med Chem Lett 11:279–282
Korani MS, Farbood Y, Sarkaki A et al (2014) Protective effects of gallic acid against chronic cerebral hypoperfusion-induced cognitive deficit and brain oxidative damage in rats. Eur J Pharmacol 733:62–67. doi:10.1016/j.ejphar.2014.03.044
Kumar RV, Bhasker S (2014) Optimizing cervical cancer care in resource-constrained developing countries by tailoring community prevention and clinical management protocol. J Cancer Policy 2:63–73
Kumar CS, Leuschner C, Doomes EE et al (2004) Efficacy of lytic peptide-bound magnetite nanoparticles in destroying breast cancer cells. J Nanosci Nanotechnol 4:245–249
Lebedyeva IO, Ostrov DA, Neubert J et al (2014) Gabapentin hybrid peptides and bioconjugates. Bioorg Med Chem 22:1479–1486
Leuschner C, Enright FM, Gawronska B, Hansel W (2003) Membrane disrupting lytic peptide conjugates destroy hormone dependent and independent breast cancer cells. Breast Cancer Res Treat 78:17–27
Lorenzón EN, Sanches PRS, Nogueira LG et al (2013) Dimerization of aurein 1.2: effects in structure, antimicrobial activity and aggregation of Cândida albicans cells. Amino Acids 44:1521–1528. doi:10.1007/s00726-013-1475-3
Lutz J-F, Börner HG (2008) Modern trends in polymer bioconjugates design. Prog Polym Sci 33:1–39
Madlener S, Illmer C, Horvath Z et al (2007) Gallic acid inhibits ribonucleotide reductase and cyclooxygenases in human HL-60 promyelocytic leukemia cells. Cancer Lett 245:156–162. doi:10.1016/j.canlet.2006.01.001
Merrifield RB (1963) Solid phase peptide synthesis 1: synthesis of a tetrapeptide. J Am Chem Soc 85:2149–2154
Mooney A, Corry AJ, O’Sullivan D et al (2009) The synthesis, structural characterization an in vitro anti-cancer activity of novel N-(3-ferrocenyl-2-naphthoyl) dipeptide ethyl esters and novel N-(6-ferrocenyl-2-naphthoyl) dipeptide ethyl esters. J Organomet Chem 694:886–894
Paredes-Gamero EJ, Martins MNC, Cappabianco FAM et al (2012) Characterization of dual effects induced by antimicrobial peptides: regulated cell death or membrane disruption. Biochim Biophys Acta 1820:1062–1072. doi:10.1016/j.bbagen.2012.02.015
Pelin M, Sosa S, Pacor S, Tubaro A, Florio C (2014) The marine toxin palytoxin induces necrotic death in HaCaT cells through a rapid mitochondrial damage. Toxicol Lett 229:440–450. doi:10.1016/j.toxlet.2014.07.022
Pennarun B, Gaidos G, Bucur O et al (2013) killerFLIP: a novel lytic peptide specifically inducing cancer cell death. Cell Death Dis 4:894. doi:10.1038/cddis.2013.401
Ran S, Downes A, Thorpe PE (2002) Increased exposure of anionic phospholipids on the surface of tumor blood vessels. Cancer Res 62:6132–6140
Rivero-Müller A, Vuorenoja S, Tuominen M et al (2007) Use of hecate–chorionic gonadotropin β conjugate in therapy of lutenizing hormone receptor expressing gonadal somatic cell tumors. Mol Cell Endocrinol 269:17–25. doi:10.1016/j.mce.2006.11.016
Rosés C, Carbajo D, Sanclimens G et al (2012) Cell-penetrating γ-peptide/antimicrobial undecapeptide conjugates with anticancer activity. Tetrahedron 68:4406–4412. doi:10.1016/j.tet.2012.02.003
Sarjit A, Wang Y, Dykes GA (2014) Antimicrobial activity of gallic acid against thermophilic Campylobacter is strain specific and associated with a loss of calcium ions. Food Microbiol 46:227–233. doi:10.1016/j.fm.2014.08.002
Shin SY, Lee SH, Yand ST, Park EJ, Lee DG, Lee MK, Eom SH, Song WK, Kim Y, Hahm KS, Kim JI (2001) Antibacterial, antitumor and hemolytic activities of α-helical antibiotic peptide, P18 and its analogs. J Peptide Res 58:504–514
Slaninová J, Mlsorá V, Kroupová H, Alán L, Tunová T, Menicová L, Borovickova L, Fucík V, Cerovsky V (2012) Toxicity study of antimicrobial peptides from wild bee venom and their analogs toward mammalian normal and cancer cell. Peptides 33:18–26
Snider C, Jayasinghe S, Hristova K, White SH (2009) MPEx: a tool for exploring membrane proteins. Protein Sci 18:2624–2628
Spector AA, Yorek MA (1985) Membrane lipid composition and cellular function. J Lipid Res 26:1015–1035
Sun J, Li Y, Ding Y et al (2014) Neuroprotective effects of gallic acid against hypoxia/reoxygenation-induced mitochondrial dysfunctions in vitro and cerebral ischemia/reperfusion injury in vivo. Brain Res 1589:126–139. doi:10.1016/j.brainres.2014.09.039
Szakács G, Paterson JK, Ludwig JA et al (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219–234. doi:10.1038/nrd1984
Utsugi T, Schroit AJ, Connor J et al (1991) Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes. Cancer Res 51:3062–3066
Vicente EF, Basso LGM, Cespedes GF et al (2013) Dynamics and conformational studies of TOAC spin labeled analogues of Ctx(Ile21)-Ha peptide from Hypsiboas albopunctatus. PLoS One. doi:10.1371/journal.pone.0060818
Vilar G, Tulla-Puche J, Alberício F (2012) Polymers and drug delivery systems. Curr Drug Deliv 9(4):367–394
Yang Q-Z, Wang C, Lang L et al (2013) Design of potent, non-toxic anticancer peptides based on the structure of the antimicrobial peptide, temporin-1CEa. Arch Pharm Res 36:1302–1310. doi:10.1007/s12272-013-0112-8
Yates C, Sharp S, Jones J et al (2011) LHRH-conjugated lytic peptides directly target prostate cancer cells. Biochem Pharmacol 81:104–110
You BR, Park WH (2010) Gallic acid-induced lung cancer cell death is related to glutathione depletion as well as reactive oxygen species increase. Toxicol Vitr 24:1356–1362. doi:10.1016/j.tiv.2010.04.009
You BR, Moon HJ, Han YH, Park WH (2010) Gallic acid inhibits the growth of HeLa cervical cancer cells via apoptosis and/or necrosis. Food Chem Toxicol 48:1334–1340. doi:10.1016/j.fct.2010.02.034