Bioactive peptides for anticancer therapies
Cancer is a serious concern in public health worldwide. Numerous modalities including surgery, radiotherapy, and chemotherapy, have been used for cancer therapies in clinic. Despite progress in anticancer therapies, the usage of these methods for cancer treatment is often related to deleterious side effects and multidrug resistance of conventional anticancer drugs, which have prompted the development of novel therapeutic methods. Anticancer peptides (ACPs), derived from naturally occurring and modified peptides, have received great attention in these years and emerge as novel therapeutic and diagnostic candidates for cancer therapies, because of several advantages over the current treatment modalities. In this review, the classification and properties of ACPs, the mode of action and mechanism of membrane disruption, as well as the natural sources of bioactive peptides with anticancer activities were summarised. Because of their high efficacy for inducing cancer cell death, certain ACPs have been developed to work as drugs and vaccines, evaluated in varied phases of clinical trials. We expect that this summary could facilitate the understanding and design of ACPs with increased specificity and toxicity towards malignant cells and with reduced side effects to normal cells.
Below is the content of the Citations in the paper which has been de-formatted, however, the content stays consistent with the original.
1. Poston, G. J. Global Cancer Surgery: The Lancet Oncology Review. *Eur J Surg Oncol.* 2015, 41, 1559-1561.
2. Norouzi, P.; Mirmohammadi, M.; Houshdar Tehrani, M. H. Anticancer Peptides Mechanisms, Simple and Complex. *Chem Biol Interact.* 2022, 368, 110194.
3. Sung, H.; Ferlay, J.; Siegel, R. L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. *CA Cancer J Clin.* 2021, 71, 209-249.
4. Hanahan, D.; Weinberg, R. A. The Hallmarks of Cancer. *Cell.* 2000, 100, 57-70.
5. Cai, Z.; Yin, Y.; Shen, C.; Wang, J.; Yin, X.; Chen, Z.; Zhou, Y.; Zhang, B. Comparative Effectiveness of Preoperative, Postoperative and Perioperative Treatments for Resectable Gastric Cancer: A Network Meta-Analysis of the Literature from the Past 20 Years. *Surg Oncol.* 2018, 27, 563-574.
6. Yu, W. D.; Sun, G.; Li, J.; Xu, J.; Wang, X. Mechanisms and Therapeutic Potentials of Cancer Immunotherapy in Combination with Radiotherapy and/or Chemotherapy. *Cancer Lett.* 2019, 452, 66-70.
7. Aljabery, F.; Shabo, I.; Gimm, O.; Jahnson, S.; Olsson, H. The Expression Profile of p14, p53 and p21 in Tumour Cells Is Associated with Disease-Specific Survival and the Outcome of Postoperative Chemotherapy Treatment in Muscle-Invasive Bladder Cancer. *Urol Oncol.* 2018, 36, 530.e7-530.e18.
8. Rajalakshmi, M.; Suveena, S.; Vijayalakshmia, P.; Indu, S.; Roy, A.; Ludas, A. DaiCee: A Database for Anti-Cancer Compounds with Targets and Side Effect Profiles. *Bioinformation.* 2020, 16, 843-848.
9. Shimizu, C. Side Effects of Anticancer Treatment and the Needs for Translational Research on Toxicity: A Clinician’s Perspective. *Nihon Yakurigaku Zasshi.* 2015, 146, 72-75.
10. Pérez-Tomás, R. Multidrug Resistance: Retrospect and Prospects in Anti-Cancer Drug Treatment. *Curr Med Chem.* 2006, 13, 1859-1876.
11. Hoekstra, R.; Verweij, J.; Eskens, F. A. Clinical Trial Design for Target Specific Anticancer Agents. *Invest New Drugs.* 2003, 21, 243-250.
12. Vulfovich, M.; Saba, N. Molecular Biological Design of Novel Antineoplastic Therapies. *Expert Opin Investig Drugs.* 2004, 13, 577-607.
13. Wang, L.; Qu, L.; Lin, S.; Yang, Q.; Zhang, X.; Jin, L.; Dong, H.; Sun, D. Biological Functions and Applications of Antimicrobial Peptides. *Curr Protein Pept Sci.* 2022, 23, 226-247.
14. Hilchie, A. L.; Hoskin, D. W.; Power Coombs, M. R. Anticancer Activities of Natural and Synthetic Peptides. *Adv Exp Med Biol.* 2019, 1117, 131-147.
15. Soon, T. N.; Chia, A. Y. Y.; Yap, W. H.; Tang, Y. Q. Anticancer Mechanisms of Bioactive Peptides. *Protein Pept Lett.* 2020, 27, 823-830.
16. Marqus, S.; Pirogova, E.; Piva, T. J. Evaluation of the Use of Therapeutic Peptides for Cancer Treatment. *J Biomed Sci.* 2017, 24, 21.
17. Chiangjong, W.; Chutipongtanate, S.; Hongeng, S. Anticancer Peptide: Physicochemical Property, Functional Aspect and Trend in Clinical Application (Review). *Int J Oncol.* 2020, 57, 678-696.
18. Vlieghe, P.; Lisowski, V.; Martinez, J.; Khrestchatisky, M. Synthetic Therapeutic Peptides: Science and Market. *Drug Discov Today.* 2010, 15, 40-56.
19. Thundimadathil, J. Cancer Treatment Using Peptides: Current Therapies and Future Prospects. *J Amino Acids.* 2012, 2012, 967347.
20. Zhang, D.; He, Y.; Ye, Y.; Ma, Y.; Zhang, P.; Zhu, H.; Xu, N.; Liang, S. Little Antimicrobial Peptides with Big Therapeutic Roles. *Protein Pept Lett.* 2019, 26, 564-578.
21. Juretić, D. Designed Multifunctional Peptides for Intracellular Targets. *Antibiotics (Basel).* 2022, 11, 1196.
22. Basith, S.; Manavalan, B.; Shin, T. H.; Lee, D. Y.; Lee, G. Evolution of Machine Learning Algorithms in the Prediction and Design of Anticancer Peptides. *Curr Protein Pept Sci.* 2020, 21, 1242-1250.
23. Palomo, J. M. Solid-Phase Peptide Synthesis: An Overview Focused on the Preparation of Biologically Relevant Peptides. *RSC Adv.* 2014, 4, 32658-32672.
24. Dai, Y.; Cai, X.; Shi, W.; Bi, X.; Su, X.; Pan, M.; Li, H.; Lin, H.; Huang, W.; Qian, H. Pro-Apoptotic Cationic Host Defense Peptides Rich in Lysine or Arginine to Reverse Drug Resistance by Disrupting Tumor Cell Membrane. *Amino Acids.* 2017, 49, 1601-1610.
25. Navarro, S.; Aleu, J.; Jiménez, M.; Boix, E.; Cuchillo, C. M.; Nogués, M. V. The Cytotoxicity of Eosinophil Cationic Protein/Ribonuclease 3 on Eukaryotic Cell Lines Takes Place Through Its Aggregation on the Cell Membrane. *Cell Mol Life Sci.* 2008, 65, 324-337.
26. Midoux, P.; Kichler, A.; Boutin, V.; Maurizot, J. C.; Monsigny, M. Membrane Permeabilization and Efficient Gene Transfer by a Peptide Containing Several Histidines. *Bioconjug Chem.* 1998, 9, 260-267.
27. Yamaguchi, Y.; Yamamoto, K.; Sato, Y.; Inoue, S.; Morinaga, T.; Hirano, E. Combination of Aspartic Acid and Glutamic Acid Inhibits Tumor Cell Proliferation. *Biomed Res.* 2016, 37, 153-159.
28. Oancea, E.; Teruel, M. N.; Quest, A. F.; Meyer, T. Green Fluorescent Protein (GFP)-Tagged Cysteine-Rich Domains from Protein Kinase C as Fluorescent Indicators for Diacylglycerol Signaling in Living Cells. *J Cell Biol.* 1998, 140, 485-498.
29. Shamova, O.; Orlov, D.; Stegemann, C.; Czihal, P.; Hoffmann, R.; Brogden, K.; Kolodkin, N.; Sakuta, G.; Tossi, A.; Sahl, H.-G.; Kokryakov, V.; Lehrer, R. I. ChBac3.4: A Novel Proline-Rich Antimicrobial Peptide from Goat Leukocytes. *Int J Pept Res Ther.* 2009, 15, 31-42.
30. Dennison, S. R.; Whittaker, M.; Harris, F.; Phoenix, D. A. Anticancer Alpha-Helical Peptides and Structure/Function Relationships Underpinning Their Interactions with Tumour Cell Membranes. *Curr Protein Pept Sci.* 2006, 7, 487-499.
31. Kawaguchi, K.; Han, Q.; Li, S.; Tan, Y.; Igarashi, K.; Kiyuna, T.; Miyake, K.; Miyake, M.; Chmielowski, B.; Nelson, S. D.; Russell, T. A.; Dry, S. M.; Li, Y.; Singh, A. S.; Eckardt, M. A.; Unno, M.; Eilber, F. C.; Hoffman, R. M. Targeting Methionine with Oral Recombinant Methioninase (o-rMETase) Arrests a Patient-Derived Orthotopic Xenograft (PDOX) Model of BRAF-V600E Mutant Melanoma: Implications for Chronic Clinical Cancer Therapy and Prevention. *Cell Cycle.* 2018, 17, 356-361.
32. Ahmaditaba, M. A.; Houshdar Tehrani, M. H.; Zarghi, A.; Shahosseini, S.; Daraei, B. Design, Synthesis and Biological Evaluation of Novel Peptide-Like Analogues as Selective COX-2 Inhibitors. *Iran J Pharm Res.* 2018, 17, 87-92.
33. Bhunia, D.; Mondal, P.; Das, G.; Saha, A.; Sengupta, P.; Jana, J.; Mohapatra, S.; Chatterjee, S.; Ghosh, S. Spatial Position Regulates Power of Tryptophan: Discovery of a Major-Groove-Specific Nuclear-Localizing, Cell-Penetrating Tetrapeptide. *J Am Chem Soc.* 2018, 140, 1697-1714.
34. Hoskin, D. W.; Ramamoorthy, A. Studies on Anticancer Activities of Antimicrobial Peptides. *Biochim Biophys Acta.* 2008, 1778, 357-375.
35. Szlasa, W.; Zendran, I.; Zalesińska, A.; Tarek, M.; Kulbacka, J. Lipid Composition of the Cancer Cell Membrane. *J Bioenerg Biomembr.* 2020, 52, 321-342.
36. Schweizer, F. Cationic Amphiphilic Peptides with Cancer-Selective Toxicity. *Eur J Pharmacol.* 2009, 625, 190-194.
37. Sok, M.; Sentjurc, M.; Schara, M. Membrane Fluidity Characteristics of Human Lung Cancer. *Cancer Lett.* 1999, 139, 215-220.
38. Zwaal, R. F.; Schroit, A. J. Pathophysiologic Implications of Membrane Phospholipid Asymmetry in Blood Cells. *Blood.* 1997, 89, 1121-1132.
39. Mai, J. C.; Mi, Z.; Kim, S. H.; Ng, B.; Robbins, P. D. A Proapoptotic Peptide for the Treatment of Solid Tumors. *Cancer Res.* 2001, 61, 7709-7712.
40. Li, H.; Kolluri, S. K.; Gu, J.; Dawson, M. I.; Cao, X.; Hobbs, P. D.; Lin, B.; Chen, G.; Lu, J.; Lin, F.; Xie, Z.; Fontana, J. A.; Reed, J. C.; Zhang, X. Cytochrome C Release and Apoptosis Induced by Mitochondrial Targeting of Nuclear Orphan Receptor TR3. *Science.* 2000, 289, 1159-1164.
41. Bouchet, S.; Tang, R.; Fava, F.; Legrand, O.; Bauvois, B. The CNGRC-GG-D(KLAKLAK)2 Peptide Induces a Caspase-Independent, Ca2+-Dependent Death in Human Leukemic Myeloid Cells by Targeting Surface Aminopeptidase N/CD13. *Oncotarget.* 2016, 7, 19445-19467.
42. Li, Y.; Yu, J. Research Progress in Structure-Activity Relationship of Bioactive Peptides. *J Med Food.* 2015, 18, 147-156.
43. Chalamaiah, M.; Yu, W.; Wu, J. Immunomodulatory and Anticancer Protein Hydrolysates (Peptides) from Food Proteins: A Review. *Food Chem.* 2018, 245, 205-222.
44. Sharma, S. V. Melittin-Induced Hyperactivation of Phospholipase A2 Activity and Calcium Influx in Ras-Transformed Cells. *Oncogene.* 1993, 8, 939-947.
45. Quintal-Bojórquez, N.; Segura-Campos, M. R. Bioactive Peptides as Therapeutic Adjuvants for Cancer. *Nutr Cancer.* 2021, 73, 1309-1321.
46. Lee, H. T.; Lee, C. C.; Yang, J. R.; Lai, J. Z.; Chang, K. Y. A Large-Scale Structural Classification of Antimicrobial Peptides. *Biomed Res Int.* 2015, 2015, 475062.
47. Libério, M. S.; Joanitti, G. A.; Fontes, W.; Castro, M. S. Anticancer Peptides and Proteins: A Panoramic View. *Protein Pept Lett.* 2013, 20, 380-391.
48. Rothbard, J. B.; Jessop, T. C.; Lewis, R. S.; Murray, B. A.; Wender, P. A. Role of Membrane Potential and Hydrogen Bonding in the Mechanism of Translocation of Guanidinium-Rich Peptides into Cells. *J Am Chem Soc.* 2004, 126, 9506-9507.
49. Guidotti, G.; Brambilla, L.; Rossi, D. Cell-Penetrating Peptides: From Basic Research to Clinics. *Trends Pharmacol Sci.* 2017, 38, 406-424.
50. Oelkrug, C.; Hartke, M.; Schubert, A. Mode of Action of Anticancer Peptides (ACPs) from Amphibian Origin. *Anticancer Res.* 2015, 35, 635-643.
51. Gabernet, G.; Müller, A. T.; Hiss, J. A.; Schneider, G. Membranolytic Anticancer Peptides. *MedChemComm.* 2016, 7, 2232-2245.
52. Huang, Y. B.; Wang, X. F.; Wang, H. Y.; Liu, Y.; Chen, Y. Studies on Mechanism of Action of Anticancer Peptides by Modulation of Hydrophobicity within a Defined Structural Framework. *Mol Cancer Ther.* 2011, 10, 416-426.
53. Lehrer, R. I.; Lichtenstein, A. K.; Ganz, T. Defensins: Antimicrobial and Cytotoxic Peptides of Mammalian Cells. *Annu Rev Immunol.* 1993, 11, 105-128.
54. Kumar, P.; Kizhakkedathu, J. N.; Straus, S. K. Antimicrobial Peptides: Diversity, Mechanism of Action and Strategies to Improve the Activity and Biocompatibility In Vivo. *Biomolecules.* 2018, 8, 4.
55. Veldhuizen, E. J.; Schneider, V. A.; Agustiandari, H.; van Dijk, A.; Tjeerdsma-van Bokhoven, J. L.; Bikker, F. J.; Haagsman, H. P. Antimicrobial and Immunomodulatory Activities of PR-39 Derived Peptides. *PLoS One.* 2014, 9, e95939.
56. Chan, Y. R.; Gallo, R. L. PR-39, a Syndecan-Inducing Antimicrobial Peptide, Binds and Affects p130(Cas). *J Biol Chem.* 1998, 273, 28978-28985.
57. Bae, S.; Oh, K.; Kim, H.; Kim, Y.; Kim, H. R.; Hwang, Y. I.; Lee, D. S.; Kang, J. S.; Lee, W. J. The Effect of Alloferon on the Enhancement of NK Cell Cytotoxicity Against Cancer via the Up-Regulation of Perforin/Granzyme B Secretion. *Immunobiology.* 2013, 218, 1026-1033.
58. Ramalho, S. D.; Pinto, M. E. F.; Ferreira, D.; Bolzani, V. S. Biologically Active Orbitides from the Euphorbiaceae Family. *Planta Med.* 2018, 84, 558-567.
59. Hu, E.; Wang, D.; Chen, J.; Tao, X. Novel Cyclotides from Hedyotis Diffusa Induce Apoptosis and Inhibit Proliferation and Migration of Prostate Cancer Cells. *Int J Clin Exp Med.* 2015, 8, 4059-4065.
60. Zhang, G.; Liu, S.; Liu, Y.; Wang, F.; Ren, J.; Gu, J.; Zhou, K.; Shan, B. A Novel Cyclic Pentapeptide, H-10, Inhibits B16 Cancer Cell Growth and Induces Cell Apoptosis. *Oncol Lett.* 2014, 8, 248-252.
61. Sable, R.; Parajuli, P.; Jois, S. Peptides, Peptidomimetics, and Polypeptides from Marine Sources: A Wealth of Natural Sources for Pharmaceutical Applications. *Mar Drugs.* 2017, 15, 124.
62. Chakrabarti, S.; Guha, S.; Majumder, K. Food-Derived Bioactive Peptides in Human Health: Challenges and Opportunities. *Nutrients.* 2018, 10, 1738.
63. Burton, M. F.; Steel, P. G. The Chemistry and Biology of LL-37. *Nat Prod Rep.* 2009, 26, 1572-1584.
64. Mader, J. S.; Mookherjee, N.; Hancock, R. E.; Bleackley, R. C. The Human Host Defense Peptide LL-37 Induces Apoptosis in a Calpain- and Apoptosis-Inducing Factor-Dependent Manner Involving Bax Activity. *Mol Cancer Res.* 2009, 7, 689-702.
65. Ganz, T.; Selsted, M. E.; Szklarek, D.; Harwig, S. S.; Daher, K.; Bainton, D. F.; Lehrer, R. I. Defensins: Natural Peptide Antibiotics of Human Neutrophils. *J Clin Invest.* 1985, 76, 1427-1435.
66. McKeown, S. T.; Lundy, F. T.; Nelson, J.; Lockhart, D.; Irwin, C. R.; Cowan, C. G.; Marley, J. J. The Cytotoxic Effects of Human Neutrophil Peptide-1 (HNP1) and Lactoferrin on Oral Squamous Cell Carcinoma (OSCC) In Vitro. *Oral Oncol.* 2006, 42, 685-690.
67. Jang, A.; Jo, C.; Kang, K.-S.; Lee, M. Antimicrobial and Human Cancer Cell Cytotoxic Effect of Synthetic Angiotensin-Converting Enzyme (ACE) Inhibitory Peptides. *Food Chem.* 2008, 107, 327-336.
68. Su, L.; Xu, G.; Shen, J.; Tuo, Y.; Zhang, X.; Jia, S.; Chen, Z.; Su, X. Anticancer Bioactive Peptide Suppresses Human Gastric Cancer Growth Through Modulation of Apoptosis and the Cell Cycle. *Oncol Rep.* 2010, 23, 3-9.
69. Yu, L.; Yang, L.; An, W.; Su, X. Anticancer Bioactive Peptide-3 Inhibits Human Gastric Cancer Growth by Suppressing Gastric Cancer Stem Cells. *J Cell Biochem.* 2014, 115, 697-711.
70. Suarez-Jimenez, G. M.; Burgos-Hernandez, A.; Ezquerra-Brauer, J. M. Bioactive Peptides and Depsipeptides with Anticancer Potential: Sources from Marine Animals. *Mar Drugs.* 2012, 10, 963-986.
71. Conlon, J. M.; Mechkarska, M.; Lukic, M. L.; Flatt, P. R. Potential Therapeutic Applications of Multifunctional Host-Defense Peptides from Frog Skin as Anti-Cancer, Anti-Viral, Immunomodulatory, and Anti-Diabetic Agents. *Peptides.* 2014, 57, 67-77.
72. Kim, M. K.; Kang, N.; Ko, S. J.; Park, J.; Park, E.; Shin, D. W.; Kim, S. H.; Lee, S. A.; Lee, J. I.; Lee, S. H.; Ha, E. G.; Jeon, S. H.; Park, Y. Antibacterial and Antibiofilm Activity and Mode of Action of Magainin 2 Against Drug-Resistant Acinetobacter Baumannii. *Int J Mol Sci.* 2018, 19, 3041.
73. Lehmann, J.; Retz, M.; Sidhu, S. S.; Suttmann, H.; Sell, M.; Paulsen, F.; Harder, J.; Unteregger, G.; Stöckle, M. Antitumor Activity of the Antimicrobial Peptide Magainin II Against Bladder Cancer Cell Lines. *Eur Urol.* 2006, 50, 141-147.
74. Hsu, K. C.; Li-Chan, E. C. Y.; Jao, C. L. Antiproliferative Activity of Peptides Prepared from Enzymatic Hydrolysates of Tuna Dark Muscle on Human Breast Cancer Cell Line MCF-7. *Food Chem.* 2011, 126, 617-622.
75. Roy, M. K.; Watanabe, Y.; Tamai, Y. Induction of Apoptosis in HL-60 Cells by Skimmed Milk Digested with a Proteolytic Enzyme from the Yeast Saccharomyces Cerevisiae. *J Biosci Bioeng.* 1999, 88, 426-432.
76. Steijns, J. M.; van Hooijdonk, A. C. Occurrence, Structure, Biochemical Properties and Technological Characteristics of Lactoferrin. *Br J Nutr.* 2000, 84 Suppl 1, S11-17.
77. Mader, J. S.; Salsman, J.; Conrad, D. M.; Hoskin, D. W. Bovine Lactoferricin Selectively Induces Apoptosis in Human Leukemia and Carcinoma Cell Lines. *Mol Cancer Ther.* 2005, 4, 612-620.
78. Yin, C. M.; Wong, J. H.; Xia, J.; Ng, T. B. Studies on Anticancer Activities of Lactoferrin and Lactoferricin. *Curr Protein Pept Sci.* 2013, 14, 492-503.
79. Wang, Z.; Zhang, X. Isolation and Identification of Anti-Proliferative Peptides from Spirulina Platensis Using Three-Step Hydrolysis. *J Sci Food Agric.* 2017, 97, 918-922.
80. Chi, C.-F.; Hu, F.-Y.; Wang, B.; Li, T.; Ding, G.-F. Antioxidant and Anticancer Peptides from the Protein Hydrolysate of Blood Clam (Tegillarca Granosa) Muscle. *J Funct Foods.* 2015, 15, 301-313.
81. Fernández-Tomé, S.; Sanchón, J.; Recio, I.; Hernández-Ledesma, B. Transepithelial Transport of Lunasin and Derived Peptides: Inhibitory Effects on the Gastrointestinal Cancer Cells Viability. *J Food Compost Anal.* 2018, 68, 101-110.
82. Luna Vital, D. A.; González de Mejía, E.; Dia, V. P.; Loarca-Piña, G. Peptides in Common Bean Fractions Inhibit Human Colorectal Cancer Cells. *Food Chem.* 2014, 157, 347-355.
83. Soares, A. M.; Zuliani, J. P. Toxins of Animal Venoms and Inhibitors: Molecular and Biotechnological Tools Useful to Human and Animal Health. *Curr Top Med Chem.* 2019, 19, 1868-1871.
84. Havas, L. J. Effect of Bee Venom on Colchicine-Induced Tumours. *Nature.* 1950, 166, 567-568.
85. Kerkis, I.; Hayashi, M. A.; Prieto da Silva, A. R.; Pereira, A.; De Sá Júnior, P. L.; Zaharenko, A. J.; Rádis-Baptista, G.; Kerkis, A.; Yamane, T. State of the Art in the Studies on Crotamine, a Cell Penetrating Peptide from South American Rattlesnake. *Biomed Res Int.* 2014, 2014, 675985.
86. Pereira, A.; Kerkis, A.; Hayashi, M. A.; Pereira, A. S.; Silva, F. S.; Oliveira, E. B.; Prieto da Silva, A. R.; Yamane, T.; Rádis-Baptista, G.; Kerkis, I. Crotamine Toxicity and Efficacy in Mouse Models of Melanoma. *Expert Opin Investig Drugs.* 2011, 20, 1189-1200.
87. Bakare, O. O.; Gokul, A.; Wu, R.; Niekerk, L. A.; Klein, A.; Keyster, M. Biomedical Relevance of Novel Anticancer Peptides in the Sensitive Treatment of Cancer. *Biomolecules.* 2021, 11, 1120.
88. Aghazadeh, H.; Memariani, H.; Ranjbar, R.; Pooshang Bagheri, K. The Activity and Action Mechanism of Novel Short Selective LL-37-Derived Anticancer Peptides Against Clinical Isolates of *Escherichia coli*. *Chem Biol Drug Des.* 2019, 93, 75-83.
89. Fruitwala, S.; El-Naccache, D. W.; Chang, T. L. Multifaceted Immune Functions of Human Defensins and Underlying Mechanisms. *Semin Cell Dev Biol.* 2019, 88, 163-172.
90. Liu, S.; Zhou, L.; Li, J.; Suresh, A.; Verma, C.; Foo, Y. H.; Yap, E. P.; Tan, D. T.; Beuerman, R. W. Linear Analogues of Human Beta-Defensin 3: Concepts for Design of Antimicrobial Peptides with Reduced Cytotoxicity to Mammalian Cells. *ChemBioChem.* 2008, 9, 964-973.
91. Zweytick, D. LTX-315 - A Promising Novel Antitumor Peptide and Immunotherapeutic Agent. *Cell Stress.* 2019, 3, 328-329.
92. Jeyamogan, S.; Khan, N. A.; Sagathevan, K.; Siddiqui, R. Sera/Organ Lysates of Selected Animals Living in Polluted Environments Exhibit Cytotoxicity Against Cancer Cell Lines. *Anticancer Agents Med Chem.* 2019, 19, 2251-2268.
93. Brady, D.; Grapputo, A.; Romoli, O.; Sandrelli, F. Insect Cecropins, Antimicrobial Peptides with Potential Therapeutic Applications. *Int J Mol Sci.* 2019, 20, 5862.
94. Pinto, I. B.; dos Santos Machado, L.; Meneguetti, B. T.; Nogueira, M. L.; Espínola Carvalho, C. M.; Roel, A. R.; Franco, O. L. Utilization of Antimicrobial Peptides, Analogues and Mimics in Creating Antimicrobial Surfaces and Bio-Materials. *Biochem Eng J.* 2019, 150, 107237.
95. Li, B.; Lyu, P.; Xie, S.; Qin, H.; Pu, W.; Xu, H.; Chen, T.; Shaw, C.; Ge, L.; Kwok, H. F. LFB: A Novel Antimicrobial Brevinin-Like Peptide from the Skin Secretion of the Fujian Large Headed Frog, *Limnonectes fujianensi*. *Biomolecules.* 2019, 9, 242.
96. Zahedifard, F.; Lee, H.; No, J. H.; Salimi, M.; Seyed, N.; Asoodeh, A.; Rafati, S. Anti-Leishmanial Activity of Brevinin 2R and Its Lauric Acid Conjugate Type Against *L. major*: In Vitro Mechanism of Actions and In Vivo Treatment Potentials. *PLoS Negl Trop Dis.* 2019, 13, e0007217.
97. Liu, Y.; Tavana, O.; Gu, W. p53 Modifications: Exquisite Decorations of the Powerful Guardian. *J Mol Cell Biol.* 2019, 11, 564-577.
98. Chen, X.; Zhang, L.; Ma, C.; Zhang, Y.; Xi, X.; Wang, L.; Zhou, M.; Burrows, J. F.; Chen, T. A Novel Antimicrobial Peptide, Ranatuerin-2PLx, Showing Therapeutic Potential in Inhibiting Proliferation of Cancer Cells. *Biosci Rep.* 2018, 38, BSR20180710.
99. Tornesello, A. L.; Borrelli, A.; Buonaguro, L.; Buonaguro, F. M.; Tornesello, M. L. Antimicrobial Peptides as Anticancer Agents: Functional Properties and Biological Activities. *Molecules.* 2020, 25, 2850.
100. Tripathi, A. K.; Kumari, T.; Harioudh, M. K.; Yadav, P. K.; Kathuria, M.; Shukla, P. K.; Mitra, K.; Ghosh, J. K. Identification of GXXXXG Motif in Chrysophsin-1 and Its Implication in the Design of Analogs with Cell-Selective Antimicrobial and Anti-Endotoxin Activities. *Sci Rep.* 2017, 7, 3384.
101. Hansen, I.; Isaksson, J.; Poth, A. G.; Hansen, K.; Andersen, A. J. C.; Richard, C. S. M.; Blencke, H. M.; Stensvåg, K.; Craik, D. J.; Haug, T. Isolation and Characterization of Antimicrobial Peptides with Unusual Disulfide Connectivity from the Colonial Ascidian *Synoicum turgens*. *Mar Drugs.* 2020, 18, 51.
102. Oren, Z.; Shai, Y. Mode of Action of Linear Amphipathic Alpha-Helical Antimicrobial Peptides. *Biopolymers.* 1998, 47, 451-463.
103. Shai, Y. Mechanism of the Binding, Insertion and Destabilization of Phospholipid Bilayer Membranes by Alpha-Helical Antimicrobial and Cell Non-Selective Membrane-Lytic Peptides. *Biochim Biophys Acta.* 1999, 1462, 55-70.
104. Matsuzaki, K.; Murase, O.; Fujii, N.; Miyajima, K. An Antimicrobial Peptide, Magainin 2, Induced Rapid Flip-Flop of Phospholipids Coupled with Pore Formation and Peptide Translocation. *Biochemistry.* 1996, 35, 11361-11368.
105. Garay, H.; Espinosa, L. A.; Perera, Y.; Sánchez, A.; Diago, D.; Perea, S. E.; Besada, V.; Reyes, O.; González, L. J. Characterization of Low-Abundance Species in the Active Pharmaceutical Ingredient of CIGB-300: A Clinical-Grade Anticancer Synthetic Peptide. *J Pept Sci.* 2018, 24, e3081.
106. Perea, S. E.; Reyes, O.; Baladron, I.; Perera, Y.; Farina, H.; Gil, J.; Rodriguez, A.; Bacardi, D.; Marcelo, J. L.; Cosme, K.; Cruz, M.; Valenzuela, C.; López-Saura, P. A.; Puchades, Y.; Serrano, J. M.; Mendoza, O.; Castellanos, L.; Sanchez, A.; Betancourt, L.; Besada, V.; Silva, R.; López, E.; Falcón, V.; Hernández, I.; Solares, M.; Santana, A.; Díaz, A.; Ramos, T.; López, C.; Ariosa, J.; González, L. J.; Garay, H.; Gómez, D.; Gómez, R.; Alonso, D. F.; Sigman, H.; Herrera, L.; Acevedo, B. CIGB-300, a Novel Proapoptotic Peptide that Impairs the CK2 Phosphorylation and Exhibits Anticancer Properties Both In Vitro and In Vivo. *Mol Cell Biochem.* 2008, 316, 163-167.
107. Rodríguez-Ulloa, A.; Ramos, Y.; Gil, J.; Perera, Y.; Castellanos-Serra, L.; García, Y.; Betancourt, L.; Besada, V.; González, L. J.; Fernández-de-Cossio, J.; Sanchez, A.; Serrano, J. M.; Farina, H.; Alonso, D. F.; Acevedo, B. E.; Padrón, G.; Musacchio, A.; Perea, S. E. Proteomic Profile Regulated by the Anticancer Peptide CIGB-300 in Non-Small Cell Lung Cancer (NSCLC) Cells. *J Proteome Res.* 2010, 9, 5473-5483.
108. Hirabayashi, K.; Yanagisawa, R.; Saito, S.; Higuchi, Y.; Koya, T.; Sano, K.; Koido, S.; Okamoto, M.; Sugiyama, H.; Nakazawa, Y.; Shimodaira, S. Feasibility and Immune Response of WT1 Peptide Vaccination in Combination with OK-432 for Paediatric Solid Tumors. *Anticancer Res.* 2018, 38, 2227-2234.
109. Yanagisawa, R.; Koizumi, T.; Koya, T.; Sano, K.; Koido, S.; Nagai, K.; Kobayashi, M.; Okamoto, M.; Sugiyama, H.; Shimodaira, S. WT1-Pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study. *Anticancer Res.* 2018, 38, 2217-2225.
110. Ohno, S.; Takano, F.; Ohta, Y.; Kyo, S.; Myojo, S.; Dohi, S.; Sugiyama, H.; Ohta, T.; Inoue, M. Frequency of Myeloid Dendritic Cells Can Predict the Efficacy of Wilms’ Tumor 1 Peptide Vaccination. *Anticancer Res.* 2011, 31, 2447-2452.
111. Ishikawa, H.; Imano, M.; Shiraishi, O.; Yasuda, A.; Peng, Y. F.; Shinkai, M.; Yasuda, T.; Imamoto, H.; Shiozaki, H. Phase I Clinical Trial of Vaccination with LY6K-Derived Peptide in Patients with Advanced Gastric Cancer. *Gastric Cancer.* 2014, 17, 173-180.
112. Vasef, M. A.; Ross, J. S.; Cohen, M. B. Telomerase Activity in Human Solid Tumors: Diagnostic Utility and Clinical Applications. *Am J Clin Pathol.* 1999, 112, S68-75.
113. Bernhardt, S. L.; Gjertsen, M. K.; Trachsel, S.; Møller, M.; Eriksen, J. A.; Meo, M.; Buanes, T.; Gaudernack, G. Telomerase Peptide Vaccination of Patients with Non-Resectable Pancreatic Cancer: A Dose Escalating Phase I/II Study. *Br J Cancer.* 2006, 95, 1474-1482.
114. Kokhaei, P.; Palma, M.; Hansson, L.; Osterborg, A.; Mellstedt, H.; Choudhury, A. Telomerase (hTERT 611-626) Serves as a Tumor Antigen in B-Cell Chronic Lymphocytic Leukemia and Generates Spontaneously Antileukemic, Cytotoxic T Cells. *Exp Hematol.* 2007, 35, 297-304.
115. Aspeslagh, S.; Awada, A.; A, S. M. P.; Aftimos, P.; Bahleda, R.; Varga, A.; Soria, J. C. Phase I Dose-Escalation Study of Plitidepsin in Combination with Bevacizumab in Patients with Refractory Solid Tumors. *Anticancer Drugs.* 2016, 27, 1021-1027.
116. Engel, J. B.; Tinneberg, H. R.; Rick, F. G.; Berkes, E.; Schally, A. V. Targeting of Peptide Cytotoxins to LHRH Receptors for Treatment of Cancer. *Curr Drug Targets.* 2016, 17, 488-494.
117. Noguchi, M.; Matsumoto, K.; Uemura, H.; Arai, G.; Eto, M.; Naito, S.; Ohyama, C.; Nasu, Y.; Tanaka, M.; Moriya, F.; Suekane, S.; Matsueda, S.; Komatsu, N.; Sasada, T.; Yamada, A.; Kakuma, T.; Itoh, K. An Open-Label, Randomized Phase II Trial of Personalized Peptide Vaccination in Patients with Bladder Cancer that Progressed after Platinum-Based Chemotherapy. *Clin Cancer Res.* 2016, 22, 54-60.
118. Brown, T. A.; Byrd, K.; Vreeland, T. J.; Clifton, G. T.; Jackson, D. O.; Hale, D. F.; Herbert, G. S.; Myers, J. W.; Greene, J. M.; Berry, J. S.; Martin, J.; Elkas, J. C.; Conrads, T. P.; Darcy, K. M.; Hamilton, C. A.; Maxwel, G. L.; Peoples, G. E. Final Analysis of a Phase I/IIa Trial of the Folate-Binding Protein-Derived E39 Peptide Vaccine to Prevent Recurrence in Ovarian and Endometrial Cancer Patients. *Cancer Med.* 2019, 8, 4678-4687.
119. Schwartzentruber, D. J.; Lawson, D. H.; Richards, J. M.; Conry, R. M.; Miller, D. M.; Treisman, J.; Gailani, F.; Riley, L.; Conlon, K.; Pockaj, B.; Kendra, K. L.; White, R. L.; Gonzalez, R.; Kuzel, T. M.; Curti, B.; Leming, P. D.; Whitman, E. D.; Balkissoon, J.; Reintgen, D. S.; Kaufman, H.; Marincola, F. M.; Merino, M. J.; Rosenberg, S. A.; Choyke, P.; Vena, D.; Hwu, P. gp100 Peptide Vaccine and Interleukin-2 in Patients with Advanced Melanoma. *N Engl J Med.* 2011, 364, 2119-2127.
120. Mikecin, A. M.; Walker, L. R.; Kuna, M.; Raucher, D. Thermally Targeted p21 Peptide Enhances Bortezomib Cytotoxicity in Androgen-Independent Prostate Cancer Cell Lines. *Anticancer Drugs.* 2014, 25, 189-199.
121. Xie, M.; Liu, D.; Yang, Y. Anti-Cancer Peptides: Classification, Mechanism of Action, Reconstruction and Modification. *Open Biol.* 2020, 10, 200004.
122. Hu, X.; Liu, S. Recent Advances Towards the Fabrication and Biomedical Applications of Responsive Polymeric Assemblies and Nanoparticle Hybrid Superstructures. *Dalton Trans.* 2015, 44, 3904-3922.
123. Hwang, J. S.; Kim, S. G.; Shin, T. H.; Jang, Y. E.; Kwon, D. H.; Lee, G. Development of Anticancer Peptides Using Artificial Intelligence and Combinational Therapy for Cancer Therapeutics. *Pharmaceutics.* 2022, 14, 997.
124. Regberg, J.; Srimanee, A.; Langel, U. Applications of Cell-Penetrating Peptides for Tumor Targeting and Future Cancer Therapies. *Pharmaceuticals (Basel).* 2012, 5, 991-1007.
125. Chatzisideri, T.; Leonidis, G.; Sarli, V. Cancer-Targeted Delivery Systems Based on Peptides. *Future Med Chem.* 2018, 10, 2201-2226.
126. Kim, B. J.; Xu, B. Enzyme-Instructed Self-Assembly for Cancer Therapy and Imaging. *Bioconjug Chem.* 2020, 31, 492-500.
127. Shi, J.; Xu, B. Nanoscale Assemblies of Small Molecules Control the Fate of Cells. *Nano Today.* 2015, 10, 615-630.
128. Liu, X.; Wu, F.; Ji, Y.; Yin, L. Recent Advances in Anti-Cancer Protein/Peptide Delivery. *Bioconjug Chem.* 2019, 30, 305-324.
129. Conibear, A. C.; Schmid, A.; Kamalov, M.; Becker, C. F. W.; Bello, C. Recent Advances in Peptide-Based Approaches for Cancer Treatment. *Curr Med Chem.* 2020, 27, 1174-1205.
