Skip to main content

Advertisement

Log in

Tumor cell membrane-targeting cationic antimicrobial peptides: novel insights into mechanisms of action and therapeutic prospects

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

There is an ongoing need for effective and targeted cancer treatments that can overcome the detrimental side effects presented by current treatment options. One class of novel anticancer molecules with therapeutic potential currently under investigation are cationic antimicrobial peptides (CAPs). CAPs are small innate immunity peptides found ubiquitously throughout nature that are typically membrane-active against a wide range of pathogenic microbes. A number of CAPs can also target mammalian cells and often display selective activity towards tumor cells, making them attractive candidates as novel anticancer agents warranting further investigation. This current and comprehensive review describes key examples of naturally occurring membrane-targeting CAPs and their modified derivatives that have demonstrated anticancer activity, across multiple species of origin and structural subfamilies. In addition, we address recent advances made in the field and the ongoing challenges faced in translating experimental findings into clinically relevant treatments.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Chu E, DeVita VT Jr, DeVita VT Jr (2015) Principles of cancer chemotherapy. Physicians’ cancer chemotherapy drug manual 2016. Jones & Bartlett Publishers, Burlington, pp 1–4

    Google Scholar 

  2. Wu Q, Yang Z, Nie Y, Shi Y, Fan D (2014) Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches. Cancer Lett 347(2):159–166

    Article  CAS  PubMed  Google Scholar 

  3. WHO (2015) Cancer fact sheet 2015. http://www.who.int/mediacentre/factsheets/fs297/en/. Accessed 1 Dec 2016

  4. Gaspar D, Castanho MA (2016) Anticancer peptides: prospective innovation in cancer therapy. Host defense peptides and their potential as therapeutic agents. Springer, Berlin, pp 95–109

    Google Scholar 

  5. Riedl S, Zweytick D, Lohner K (2011) Membrane-active host defense peptides—challenges and perspectives for the development of novel anticancer drugs. Chem Phys Lipid 164(8):766–781

    Article  CAS  Google Scholar 

  6. Phoenix DA, Dennison SR, Harris F (2013) Cationic antimicrobial peptides. Antimicrobial Peptides, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, pp 39–81

  7. Hancock RE, Diamond G (2000) The role of cationic antimicrobial peptides in innate host defences. Trends Microbiol 8(9):402–410

    Article  CAS  PubMed  Google Scholar 

  8. Brogden KA (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 3(3):238–250

    Article  CAS  PubMed  Google Scholar 

  9. Mader JS, Hoskin DW (2006) Cationic antimicrobial peptides as novel cytotoxic agents for cancer treatment. Expert Opin Investig Drugs 15(8):933–946

    Article  CAS  PubMed  Google Scholar 

  10. Chen J-Y, Lin W-J, Wu J-L, Her GM, Hui C-F (2009) Epinecidin-1 peptide induces apoptosis which enhances antitumor effects in human leukemia U937 cells. Peptides 30(12):2365–2373

    Article  CAS  PubMed  Google Scholar 

  11. Mader JS, Richardson A, Salsman J, Top D, de Antueno R, Duncan R et al (2007) Bovine lactoferricin causes apoptosis in Jurkat T-leukemia cells by sequential permeabilization of the cell membrane and targeting of mitochondria. Exp Cell Res 313(12):2634–2650

    Article  CAS  PubMed  Google Scholar 

  12. Rozek A, Pocwers JP-S, Friedrich CL, Hancock RE (2003) Structure-based design of an indolicidin peptide analogue with increased protease stability. Biochemistry 42(48):14130–14138

    Article  CAS  PubMed  Google Scholar 

  13. Fahrner RL, Dieckmann T, Harwig SS, Lehrer RI, Eisenberg D, Feigon J (1996) Solution structure of protegrin-1, a broad-spectrum antimicrobial peptide from porcine leukocytes. Chem Biol 3(7):543–550

    Article  CAS  PubMed  Google Scholar 

  14. Conibear AC, Rosengren KJ, Harvey PJ, Craik DJ (2012) Structural characterization of the cyclic cystine ladder motif of θ-defensins. Biochemistry 51(48):9718–9726

    Article  CAS  PubMed  Google Scholar 

  15. Hoover DM, Rajashankar KR, Blumenthal R, Puri A, Oppenheim JJ, Chertov O et al (2000) The structure of human β-defensin-2 shows evidence of higher order oligomerization. J Biol Chem 275(42):32911–32918

    Article  CAS  PubMed  Google Scholar 

  16. Poon IK, Baxter AA, Lay FT, Mills GD, Adda CG, Payne JA et al (2014) Phosphoinositide-mediated oligomerization of a defensin induces cell lysis. eLife 3:e01808

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Schrödinger (2016) PyMOL Molecular Graphics System, Version 1.8

  18. Wang G, Li X, Wang Z (2016) APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res 44(D1):D1087–D1093

    Article  CAS  PubMed  Google Scholar 

  19. Hancock RE, Sahl H-G (2006) Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 24(12):1551–1557

    Article  CAS  PubMed  Google Scholar 

  20. Yin LM, Edwards MA, Li J, Yip CM, Deber CM (2012) Roles of hydrophobicity and charge distribution of cationic antimicrobial peptides in peptide-membrane interactions. J Biol Chem 287(10):7738–7745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ran S, Downes A, Thorpe PE (2002) Increased exposure of anionic phospholipids on the surface of tumor blood vessels. Can Res 62(21):6132–6140

    CAS  Google Scholar 

  22. Balasubramanian K, Schroit AJ (2003) Aminophospholipid asymmetry: a matter of life and death. Annu Rev Physiol 65(1):701–734

    Article  CAS  PubMed  Google Scholar 

  23. Ran S, Thorpe PE (2002) Phosphatidylserine is a marker of tumor vasculature and a potential target for cancer imaging and therapy. Int J Radiat Oncol Biol Phys 54(5):1479–1484

    Article  CAS  PubMed  Google Scholar 

  24. Lima LG, Monteiro RQ (2013) Activation of blood coagulation in cancer: implications for tumour progression. Biosci Rep 33(5):701–710

    Article  CAS  Google Scholar 

  25. Schröder-Borm H, Bakalova R, Andrä J (2005) The NK-lysin derived peptide NK-2 preferentially kills cancer cells with increased surface levels of negatively charged phosphatidylserine. FEBS Lett 579(27):6128–6134

    Article  PubMed  CAS  Google Scholar 

  26. Riedl S, Rinner B, Schaider H, Lohner K, Zweytick D (2014) Killing of melanoma cells and their metastases by human lactoferricin derivatives requires interaction with the cancer marker phosphatidylserine. Biometals 27(5):981–997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Matsuzaki K, Harada M, Handa T, Funakoshi S, Fujii N, Yajima H et al (1989) Magainin 1-induced leakage of entrapped calcein out of negatively-charged lipid vesicles. Biochim Biophys Acta Biomembr 981(1):130–134

    Article  CAS  Google Scholar 

  28. Iwasaki T, Ishibashi J, Tanaka H, Sato M, Asaoka A, Taylor D et al (2009) Selective cancer cell cytotoxicity of enantiomeric 9-mer peptides derived from beetle defensins depends on negatively charged phosphatidylserine on the cell surface. Peptides 30(4):660–668

    Article  CAS  PubMed  Google Scholar 

  29. Riedl S, Leber R, Rinner B, Schaider H, Lohner K, Zweytick D (2015) Human lactoferricin derived di-peptides deploying loop structures induce apoptosis specifically in cancer cells through targeting membranous phosphatidylserine. Biochim Biophys Acta Biomembr 1848(11):2918–2931

    Article  CAS  Google Scholar 

  30. Kufe DW (2009) Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer 9(12):874–885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Raman K, Kuberan B (2010) Chemical tumor biology of heparan sulfate proteoglycans. Curr Chem Biol 4(1):20

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Sok M, Šentjurc M, Schara M (1999) Membrane fluidity characteristics of human lung cancer. Cancer Lett 139(2):215–220

    Article  CAS  PubMed  Google Scholar 

  33. Deliconstantinos G (1986) Physiological aspects of membrane lipid fluidity in malignancy. Anticancer Res 7(5B):1011–1021

    Google Scholar 

  34. Zeisig R, Koklič T, Wiesner B, Fichtner I, Sentjurč M (2007) Increase in fluidity in the membrane of MT3 breast cancer cells correlates with enhanced cell adhesion in vitro and increased lung metastasis in NOD/SCID mice. Arch Biochem Biophys 459(1):98–106

    Article  CAS  PubMed  Google Scholar 

  35. Taraboletti G, Perin L, Bottazzi B, Mantovani A, Giavazzi R, Salmona M (1989) Membrane fluidity affects tumor-cell motility, invasion and lung-colonizing potential. Int J Cancer 44(4):707–713

    Article  CAS  PubMed  Google Scholar 

  36. Chen HM, Wang W, Smith D, Chan SC (1997) Effects of the anti-bacterial peptide cecropin B and its analogs, cecropins B-1 and B-2, on liposomes, bacteria, and cancer cells. Biochim Biophys Acta Gen Subj. 1336(2):171–179

    Article  CAS  Google Scholar 

  37. Chaudhary J, Munshi M (1995) Scanning electron microscopic analysis of breast aspirates. Cytopathology 6(3):162–167

    Article  CAS  PubMed  Google Scholar 

  38. Ren J, Ji Hamada, Okada F, Takeichi N, Morikawa K, Hosokawa M et al (1990) Correlation between the presence of microvilli and the growth or metastatic potential of tumor cells. Jpn J Cancer Res 81(9):920–926

    Article  CAS  PubMed  Google Scholar 

  39. Turner J, Cho Y, Dinh N-N, Waring AJ, Lehrer RI (1998) Activities of LL-37, a cathelin-associated antimicrobial peptide of human neutrophils. Antimicrob Agents Chemother 42(9):2206–2214

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Gordon YJ, Huang LC, Romanowski EG, Yates KA, Proske RJ, McDermott AM (2005) Human cathelicidin (LL-37), a multifunctional peptide, is expressed by ocular surface epithelia and has potent antibacterial and antiviral activity. Curr Eye Res 30(5):385–394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Niyonsaba F, Iwabuchi K, Someya A, Hirata M, Matsuda H, Ogawa H et al (2002) A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis. Immunology 106(1):20–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Carretero M, Escámez MJ, García M, Duarte B, Holguín A, Retamosa L et al (2008) In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37. J Investig Dermatol 128(1):223–236

    Article  CAS  PubMed  Google Scholar 

  43. Xhindoli D, Pacor S, Guida F, Antcheva N, Tossi A (2014) Native oligomerization determines the mode of action and biological activities of human cathelicidin LL-37. Biochem J 457(2):263–275

    Article  CAS  PubMed  Google Scholar 

  44. Xhindoli D, Pacor S, Benincasa M, Scocchi M, Gennaro R, Tossi A (2016) The human cathelicidin LL-37—a pore-forming antibacterial peptide and host-cell modulator. Biochim Biophys Acta Biomembr 1858(3):546–566

    Article  CAS  Google Scholar 

  45. Mader JS, Mookherjee N, Hancock RE, Bleackley RC (2009) The human host defense peptide LL-37 induces apoptosis in a calpain-and apoptosis-inducing factor-dependent manner involving bax activity. Mol Cancer Res 7(5):689–702

    Article  CAS  PubMed  Google Scholar 

  46. Risso A, Zanetti M, Gennaro R (1998) Cytotoxicity and apoptosis mediated by two peptides of innate immunity. Cell Immunol 189(2):107–115

    Article  CAS  PubMed  Google Scholar 

  47. Risso A, Braidot E, Sordano MC, Vianello A, Macrì F, Skerlavaj B et al (2002) BMAP-28, an antibiotic peptide of innate immunity, induces cell death through opening of the mitochondrial permeability transition pore. Mol Cell Biol 22(6):1926–1935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Baker MA, Maloy WL, Zasloff M, Jacob LS (1993) Anticancer efficacy of Magainin2 and analogue peptides. Can Res 53(13):3052–3057

    CAS  Google Scholar 

  49. Koszałka P, Kamysz E, Wejda M, Kamysz W, Bigda J (2011) Antitumor activity of antimicrobial peptides against U937 histiocytic cell line. Acta Biochim Pol 58(1):111–117

    PubMed  Google Scholar 

  50. Bessalle R, Kapitkovsky A, Gorea A, Shalit I, Fridkin M (1990) All-d-magainin: chirality, antimicrobial activity and proteolytic resistance. FEBS Lett 274(1):151–155

    CAS  PubMed  Google Scholar 

  51. Bland JM, De Lucca AJ, Jacks TJ, Vigo CB (2001) All-d-cecropin B: synthesis, conformation, lipopolysaccharide binding, and antibacterial activity. Mol Cell Biochem 218(1):105–111

    Article  CAS  PubMed  Google Scholar 

  52. Liu S, Yang H, Wan L, H-w Cai, S-f Li, Y-p Li et al (2011) Enhancement of cytotoxicity of antimicrobial peptide magainin II in tumor cells by bombesin-targeted delivery. Acta Pharmacol Sin 32(1):79–88

    Article  PubMed  CAS  Google Scholar 

  53. Yin Z-X, He W, Chen W-J, Yan J-H, Yang J-N, Chan S-M et al (2006) Cloning, expression and antimicrobial activity of an antimicrobial peptide, epinecidin-1, from the orange-spotted grouper, Epinephelus coioides. Aquaculture 253(1):204–211

    Article  CAS  Google Scholar 

  54. Lin W-J, Chien Y-L, Pan C-Y, Lin T-L, Chen J-Y, Chiu S-J et al (2009) Epinecidin-1, an antimicrobial peptide from fish (Epinephelus coioides) which has an antitumor effect like lytic peptides in human fibrosarcoma cells. Peptides 30(2):283–290

    Article  CAS  PubMed  Google Scholar 

  55. Suttmann H, Retz M, Paulsen F, Harder J, Zwergel U, Kamradt J et al (2008) Antimicrobial peptides of the Cecropin-family show potent antitumor activity against bladder cancer cells. BMC Urol 8(1):5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Jin X-B, Wang Y-J, Liang L-L, Pu Q-H, Shen J, Lu X-M et al (2014) Cecropin suppresses human hepatocellular carcinoma BEL-7402 cell growth and survival in vivo without side-toxicity. Asian Pac J Cancer Prev 15(13):5433

    Article  PubMed  Google Scholar 

  57. Gajski G, Garaj-Vrhovac V (2013) Melittin: a lytic peptide with anticancer properties. Environ Toxicol Pharmacol 36(2):697–705

    Article  CAS  PubMed  Google Scholar 

  58. Killion JJ, Dunn JD (1986) Differential cytolysis of murine spleen, bone-marrow and leukemia cells by melittin reveals differences in membrane topography. Biochem Biophys Res Commun 139(1):222–227

    Article  CAS  PubMed  Google Scholar 

  59. Midoux P, Mayer R, Monsigny M (1995) Membrane permeabilization by α-helical peptides: a flow cytometry study. Biochim Biophys Acta Biomembr 1239(2):249–256

    Article  Google Scholar 

  60. Andreu D, Ubach J, Boman A, Wåhlin B, Wade D, Merrifield R et al (1992) Shortened cecropin A-melittin hybrids significant size reduction retains potent antibiotic activity. FEBS Lett 296(2):190–194

    Article  CAS  PubMed  Google Scholar 

  61. Schlamadinger DE, Wang Y, McCammon JA, Kim JE (2012) Spectroscopic and computational study of melittin, cecropin A, and the hybrid peptide CM15. J Phys Chem B 116(35):10600–10608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sun D, Sun M, Zhu W, Wang Z, Li Y, Ma J (2015) The anti-cancer potency and mechanism of a novel tumor-activated fused toxin. DLM Toxins 7(2):423–438

    Article  CAS  PubMed  Google Scholar 

  63. Mader JS, Salsman J, Conrad DM, Hoskin DW (2005) Bovine lactoferricin selectively induces apoptosis in human leukemia and carcinoma cell lines. Mol Cancer Ther 4(4):612–624

    Article  CAS  PubMed  Google Scholar 

  64. Pan W-R, Chen P-W, Chen Y-L, Hsu H-C, Lin C-C, Chen W-J (2013) Bovine lactoferricin B induces apoptosis of human gastric cancer cell line AGS by inhibition of autophagy at a late stage. J Dairy Sci 96(12):7511–7520

    Article  CAS  PubMed  Google Scholar 

  65. Yoo YC, Watanabe S, Watanabe R, Hata K, Shimazaki KI, Azuma I (1997) Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibit tumor metastasis in mice. Jpn J Cancer Res 88(2):184–190

    Article  CAS  PubMed  Google Scholar 

  66. Eliassen LT, Berge G, Leknessund A, Wikman M, Lindin I, Løkke C et al (2006) The antimicrobial peptide, lactoferricin B, is cytotoxic to neuroblastoma cells in vitro and inhibits xenograft growth in vivo. Int J Cancer 119(3):493–500

    Article  CAS  PubMed  Google Scholar 

  67. Solarte VA, Conget P, Vernot J-P, Rosas JE, Rivera ZJ, García JE et al (2017) A tetrameric peptide derived from bovine lactoferricin as a potential therapeutic tool for oral squamous cell carcinoma: a preclinical model. PLoS One 12(3):e0174707

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Soletti RC, Del Barrio L, Daffre S, Miranda A, Borges HL, Moura-Neto V et al (2010) Peptide gomesin triggers cell death through l-type channel calcium influx, MAPK/ERK, PKC and PI3K signaling and generation of reactive oxygen species. Chem Biol Interact 186(2):135–143

    Article  CAS  PubMed  Google Scholar 

  69. Rodrigues EG, Dobroff AS, Cavarsan CF, Paschoalin T, Nimrichter L, Mortara RA et al (2008) Effective topical treatment of subcutaneous murine B16F10-Nex2 melanoma by the antimicrobial peptide gomesin. Neoplasia 10(1):61–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chen Y, Xu X, Hong S, Chen J, Liu N, Underhill CB et al (2001) RGD-Tachyplesin inhibits tumor growth. Can Res 61(6):2434–2438

    CAS  Google Scholar 

  71. Chen J, Xu X-M, Underhill CB, Yang S, Wang L, Chen Y et al (2005) Tachyplesin activates the classic complement pathway to kill tumor cells. Can Res 65(11):4614–4622

    Article  CAS  Google Scholar 

  72. Lichtenstein A, Ganz T, Selsted M, Lehrer R (1986) In vitro tumor cell cytolysis mediated by peptide defensins of human and. Blood 68(6):1407–1410

    CAS  PubMed  Google Scholar 

  73. Hill CP, Yee J, Selsted ME, Eisenberg D (1991) Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization. Science 251(5000):1481–1485

    Article  CAS  PubMed  Google Scholar 

  74. Szyk A, Wu Z, Tucker K, Yang D, Lu W, Lubkowski J (2006) Crystal structures of human α-defensins HNP4, HD5, and HD6. Protein Sci 15(12):2749–2760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Xu N, Y-s Wang, W-b Pan, Xiao B, Y-j Wen, X-c Chen et al (2008) Human α-defensin-1 inhibits growth of human lung adenocarcinoma xenograft in nude mice. Mol Cancer Ther 7(6):1588–1597

    Article  CAS  PubMed  Google Scholar 

  76. Terras FR, Eggermont K, Kovaleva V, Raikhel NV, Osborn RW, Kester A et al (1995) Small cysteine-rich antifungal proteins from radish: their role in host defense. Plant Cell 7(5):573–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cornet B, Bonmatin J-M, Hetru C, Hoffmann JA, Ptak M, Vovelle F (1995) Refined three-dimensional solution structure of insect defensin A. Structure 3(5):435–448

    Article  CAS  PubMed  Google Scholar 

  78. Thomma BP, Cammue BP, Thevissen K (2002) Plant defensins. Planta 216(2):193–202

    Article  CAS  PubMed  Google Scholar 

  79. Wong JH, Ng TB (2005) Sesquin, a potent defensin-like antimicrobial peptide from ground beans with inhibitory activities toward tumor cells and HIV-1 reverse transcriptase. Peptides 26(7):1120–1126

    Article  CAS  PubMed  Google Scholar 

  80. Wong JH, Ng TB (2005) Lunatusin, a trypsin-stable antimicrobial peptide from lima beans (Phaseolus lunatus L.). Peptides 26(11):2086–2092

    Article  CAS  PubMed  Google Scholar 

  81. Wang H, Ng T (2007) Isolation and characterization of an antifungal peptide with antiproliferative activity from seeds of Phaseolus vulgaris cv. ‘Spotted Bean’. Appl Microbiol Biotechnol 74(1):125–130

    Article  CAS  PubMed  Google Scholar 

  82. Lin P, Wong JH, Ng TB (2010) A defensin with highly potent antipathogenic activities from the seeds of purple pole bean. Biosci Rep 30(2):101–109

    Article  CAS  Google Scholar 

  83. Baxter AA, Richter V, Lay FT, Poon IK, Adda CG, Veneer PK et al (2015) The tomato defensin TPP3 binds phosphatidylinositol (4,5)-bisphosphate via a conserved dimeric cationic grip conformation to mediate cell lysis. Mol Cell Biol 35(11):1964–1978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Payne JA, Bleackley MR, Lee T-H, Shafee TM, Poon IK, Hulett MD et al (2016) The plant defensin NaD1 introduces membrane disorder through a specific interaction with the lipid, phosphatidylinositol 4,5 bisphosphate. Biochim Biophys Acta Biomembr 1858(6):1099–1109

    Article  CAS  Google Scholar 

  85. Baxter AA, Poon IK, Hulett MD (2017) The plant defensin NaD1 induces tumor cell death via a non-apoptotic, membranolytic process. Cell Death Discov 3:16102

    Article  PubMed  PubMed Central  Google Scholar 

  86. Kvansakul M, Lay FT, Adda CG, Veneer PK, Baxter AA, Phan TK et al (2016) Binding of phosphatidic acid by NsD7 mediates the formation of helical defensin–lipid oligomeric assemblies and membrane permeabilization. Proc Natl Acad Sci 113(40):11202–11207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bleackley MR, Payne JA, Hayes BM, Durek T, Craik DJ, Shafee TM et al (2016) Nicotiana alata defensin chimeras reveal differences in the mechanism of fungal and tumour cell killing and an enhanced antifungal variant. Antimicrob Agents Chemother 60(10):6302–6312

    Article  PubMed  PubMed Central  Google Scholar 

  88. Phan TK, Lay FT, Poon IK, Hinds MG, Kvansakul M, Hulett MD (2016) Human β-defensin 3 contains an oncolytic motif that binds PI(4,5)P2 to mediate tumour cell permeabilisation. Oncotarget 7(2):2054

    Article  PubMed  Google Scholar 

  89. Shafee TM, Lay FT, Hulett MD, Anderson MA (2016) The defensins consist of two independent, convergent protein superfamilies. Mol Biol Evol 33(9):2345–2356

    Article  CAS  PubMed  Google Scholar 

  90. Shafee TM, Lay FT, Phan TK, Anderson MA, Hulett MD (2016) Convergent evolution of defensin sequence, structure and function. Cell Mol Life Sci 74(4):663–682

    Article  PubMed  CAS  Google Scholar 

  91. Nguyen LT, Chau JK, Perry NA, De Boer L, Zaat S, Vogel HJ (2010) Serum stabilities of short tryptophan-and arginine-rich antimicrobial peptide analogs. PLoS One 5(9):e12684

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Molhoek EM, Van Dijk A, Veldhuizen EJ, Haagsman HP, Bikker FJ (2011) Improved proteolytic stability of chicken cathelicidin-2 derived peptides by d-amino acid substitutions and cyclization. Peptides 32(5):875–880

    Article  CAS  PubMed  Google Scholar 

  93. Hilchie AL, Haney EF, Pinto DM, Hancock RE, Hoskin DW (2015) Enhanced killing of breast cancer cells by a d-amino acid analog of the winter flounder-derived pleurocidin NRC-03. Exp Mol Pathol 99(3):426–434

    Article  CAS  PubMed  Google Scholar 

  94. Mygind PH, Fischer RL, Schnorr KM, Hansen MT, Sönksen CP, Ludvigsen S et al (2005) Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus. Nature 437(7061):975–980

    Article  CAS  PubMed  Google Scholar 

  95. Zhang Y, Teng D, Mao R, Wang X, Xi D, Hu X et al (2014) High expression of a plectasin-derived peptide NZ2114 in Pichia pastoris and its pharmacodynamics, postantibiotic and synergy against Staphylococcus aureus. Appl Microbiol Biotechnol 98(2):681–694

    Article  CAS  PubMed  Google Scholar 

  96. Li D, Qin Q, Wang X-Y, Shi H-S, Luo M, Guo F-C et al (2014) Intratumoral expression of mature human neutrophil peptide-1 potentiates the therapeutic effect of doxorubicin in a mouse 4T1 breast cancer model. Oncol Rep 31(3):1287–1295

    Article  CAS  PubMed  Google Scholar 

  97. Winder D, Günzburg WH, Erfle V, Salmons B (1998) Expression of antimicrobial peptides has an antitumour effect in human cells. Biochem Biophys Res Commun 242(3):608–612

    Article  CAS  PubMed  Google Scholar 

  98. Qian C-Y, Wang K-L, Fang F-F, Gu W, Huang F, Wang F-Z et al (2015) Triple-controlled oncolytic adenovirus expressing melittin to exert inhibitory efficacy on hepatocellular carcinoma. Int J Clin Exp Pathol 8(9):10403

    PubMed  PubMed Central  Google Scholar 

  99. Papo N, Shahar M, Eisenbach L, Shai Y (2003) A novel lytic peptide composed of dl-amino acids selectively kills cancer cells in culture and in mice. J Biol Chem 278(23):21018–21023

    Article  CAS  PubMed  Google Scholar 

  100. Huang Y, He L, Li G, Zhai N, Jiang H, Chen Y (2014) Role of helicity of α-helical antimicrobial peptides to improve specificity. Protein Cell 5(8):631–642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kohno M, Horibe T, Haramoto M, Yano Y, Ohara K, Nakajima O et al (2011) A novel hybrid peptide targeting EGFR-expressing cancers. Eur J Cancer 47(5):773–783

    Article  CAS  PubMed  Google Scholar 

  102. Li H, Anuwongcharoen N, Malik AA, Prachayasittikul V, Wikberg JE, Nantasenamat C (2016) Roles of d-amino acids on the bioactivity of host defense peptides. Int J Mol Sci 17(7):1023

    Article  PubMed Central  CAS  Google Scholar 

  103. Ren SX, Shen J, Cheng AS, Lu L, Chan RL, Li ZJ et al (2013) FK-16 derived from the anticancer peptide LL-37 induces caspase-independent apoptosis and autophagic cell death in colon cancer cells. PLoS One 8(5):e63641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wang H, Ke M, Tian Y, Wang J, Li B, Wang Y et al (2013) BF-30 selectively inhibits melanoma cell proliferation via cytoplasmic membrane permeabilization and DNA-binding in vitro and in B16F10-bearing mice. Eur J Pharmacol 707(1):1–10

    Article  CAS  PubMed  Google Scholar 

  105. Tian Y, Wang H, Li B, Ke M, Wang J, Dou J et al (2013) The cathelicidin-BF Lys16 mutant Cbf-K16 selectively inhibits non-small cell lung cancer proliferation in vitro. Oncol Rep 30(5):2502–2510

    Article  CAS  PubMed  Google Scholar 

  106. Lehmann J, Retz M, Sidhu SS, Suttmann H, Sell M, Paulsen F et al (2006) Antitumor activity of the antimicrobial peptide magainin II against bladder cancer cell lines. Eur Urol 50(1):141–147

    Article  CAS  PubMed  Google Scholar 

  107. Ohsaki Y, Gazdar AF, Chen H-C, Johnson BE (1992) Antitumor activity of magainin analogues against human lung cancer cell lines. Can Res 52(13):3534–3538

    CAS  Google Scholar 

  108. Liu S, Yang H, Wan L, Cheng J, Lu X (2013) Penetratin-mediated delivery enhances the antitumor activity of the cationic antimicrobial peptide magainin II. Cancer Biother Radiopharm 28(4):289–297

    Article  CAS  PubMed  Google Scholar 

  109. Lee HS, Park CB, Kim JM, Jang SA, Park IY, Kim MS et al (2008) Mechanism of anticancer activity of buforin IIb, a histone H2A-derived peptide. Cancer Lett 271(1):47–55

    Article  CAS  PubMed  Google Scholar 

  110. Chen J-Y, Lin W-J, Lin T-L (2009) A fish antimicrobial peptide, tilapia hepcidin TH2-3, shows potent antitumor activity against human fibrosarcoma cells. Peptides 30(9):1636–1642

    Article  CAS  PubMed  Google Scholar 

  111. Hilchie AL, Doucette CD, Pinto DM, Patrzykat A, Douglas S, Hoskin DW (2011) Pleurocidin-family cationic antimicrobial peptides are cytolytic for breast carcinoma cells and prevent growth of tumor xenografts. Breast Cancer Res 13(5):1

    Article  CAS  Google Scholar 

  112. Wang C, Tian L-L, Li S, Li H-B, Zhou Y, Wang H et al (2013) Rapid cytotoxicity of antimicrobial peptide tempoprin-1CEa in breast cancer cells through membrane destruction and intracellular calcium mechanism. PLoS One 8(4):e60462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Wang C, Zhou Y, Li S, Li H, Tian L, Wang H et al (2013) Anticancer mechanisms of temporin-1CEa, an amphipathic α-helical antimicrobial peptide, in Bcap-37 human breast cancer cells. Life Sci 92(20):1004–1014

    Article  CAS  PubMed  Google Scholar 

  114. Cerón JM, Contreras-Moreno J, Puertollano E, De Cienfuegos GA, Puertollano MA, De Pablo MA (2010) The antimicrobial peptide cecropin A induces caspase-independent cell death in human promyelocytic leukemia cells. Peptides 31(8):1494–1503

    Article  PubMed  CAS  Google Scholar 

  115. Jin X, Mei H, Li X, Ma Y, A-H Zeng, Wang Y et al (2010) Apoptosis-inducing activity of the antimicrobial peptide cecropin of Musca domestica in human hepatocellular carcinoma cell line BEL-7402 and the possible mechanism. Acta Biochim Biophys Sin 42(2):259–265

    Article  CAS  PubMed  Google Scholar 

  116. McKeown ST, Lundy FT, Nelson J, Lockhart D, Irwin CR, Cowan CG et al (2006) The cytotoxic effects of human neutrophil peptide-1 (HNP1) and lactoferrin on oral squamous cell carcinoma (OSCC) in vitro. Oral Oncol 42(7):685–690

    Article  CAS  PubMed  Google Scholar 

  117. Barker E, Reisfeld RA (1993) A mechanism for neutrophil-mediated lysis of human neuroblastoma cells. Can Res 53(2):362–367

    CAS  Google Scholar 

  118. Furlong SJ, Mader JS, Hoskin DW (2006) Lactoferricin-induced apoptosis in estrogen-nonresponsive MDA-MB-435 breast cancer cells is enhanced by C6 ceramide or tamoxifen. Oncol Rep 15(5):1385–1390

    CAS  PubMed  Google Scholar 

  119. Furlong SJ, Ridgway ND, Hoskin DW (2008) Modulation of ceramide metabolism in T-leukemia cell lines potentiates apoptosis induced by the cationic antimicrobial peptide bovine lactoferricin. Int J Oncol 32(3):537–544

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Amy A. Baxter.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baxter, A.A., Lay, F.T., Poon, I.K.H. et al. Tumor cell membrane-targeting cationic antimicrobial peptides: novel insights into mechanisms of action and therapeutic prospects. Cell. Mol. Life Sci. 74, 3809–3825 (2017). https://doi.org/10.1007/s00018-017-2604-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-017-2604-z

Keywords

Navigation