Coadministration of kla peptide with HPRP-A1 to enhance anticancer activity

Autoři: Wenjing Hao aff001;  Cuihua Hu aff003;  Yibing Huang aff001;  Yuxin Chen aff001
Působiště autorů: Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun, China aff001;  School of Life Sciences, Jilin University, Changchun, China aff002;  Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun, China aff003;  International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun, China aff004;  JiangsuProteLight Pharmaceutical & Biotechnology Co., Ltd., Jiangyin, China aff005
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223738


The apoptosis-inducing peptide kla (KLAKLAK)2 possesses the ability to disrupt mitochondrial membranes and induce cancer cell apoptosis, but this peptide has a poor eukaryotic cell-penetrating potential. Thus, it requires the assistance of other peptides for effective translocation at micromolar concentrations. In this study, breast and lung cancer cells were treated by kla peptide co-administrated with membrane-active anticancer peptide HPRP-A1. HPRP-A1 assisted kla to enter cancer cells and localized on mitochondrial membranes to result in cytochrome C releasing and mitochondrial depolarization which ultimately induced apoptosis.The apoptosis rate was up to 65%and 45% on MCF-7 and A549 cell lines, respectively, induced by HPRP-A1 coadministration with kla group. The breast cancer model was constructed in mice, and the anticancer peptides were injected to observe the changes in cancer volume, andimmunohistochemical analysis was performed on the tissues and organs after the drug was administered. Both the weight and volume of tumor tissue were remarkable lower in HPRP-A1 with kla group compared with thosepeptidealonggroups. The results showed that the combined drug group effectively inhibited the growth of cancer and did not cause toxic damage to normal tissues, as well as exhibited significantly improvement on peptide anticancer activity in vitro and in vivo.

Klíčová slova:

Apoptosis – Cancer treatment – Cell membranes – Mitochondria – Mouse models – Polypeptides – Toxicity – Mitochondrial membrane


1. Zhao J, Hao XY, Liu D, Huang YB, Chen YX. In vitro Characterization of the Rapid Cytotoxicity of Anticancer Peptide HPRP-A2 through Membrane Destruction and Intracellular Mechanism against Gastric Cancer Cell Lines. Plos One. 2015;10(9). ARTN e013957810.1371/journal.pone.0139578. WOS:000362175700130.

2. Al-Benna S, Shai Y, Jacobsen F, Steinstraesser L. Oncolytic Activities of Host Defense Peptides. Int J Mol Sci. 2011;12(11):8027–51. doi: 10.3390/ijms12118027 WOS:000297696100051. 22174648

3. Huang YB, Feng Q, Yan QY, Hao XY, Chen YX. Alpha-Helical Cationic Anticancer Peptides: A Promising Candidate for Novel Anticancer Drugs. Mini-Rev Med Chem. 2015;15(1):73–81. doi: 10.2174/1389557514666141107120954 WOS:000350752300009. 25382016

4. Riedl S, Zweytick D, Lohner K. Membrane-active host defense peptides—Challenges and perspectives for the development of novel anticancer drugs. Chem Phys Lipids. 2011;164(8):766–81. doi: 10.1016/j.chemphyslip.2011.09.004 WOS:000297958000008. 21945565

5. Brogden KA. Antimicrobial peptides: Pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol. 2005;3(3):238–50. doi: 10.1038/nrmicro1098 WOS:000227256700014. 15703760

6. Gaspar D, Veiga AS, Castanho MRB. From antimicrobial to anticancer peptides. A review. Front Microbiol. 2013;4. ARTN 294 10.3389/fmicb.2013.00294. WOS:000331514900002.

7. Papo N, Shai Y. Host defense peptides as new weapons in cancer treatment. Cell Mol Life Sci. 2005;62(7–8):784–90. doi: 10.1007/s00018-005-4560-2 WOS:000232496500008. 15868403

8. Hoskin DW, Ramamoorthy A. Studies on anticancer activities of antimicrobial peptides. Bba-Biomembranes. 2008;1778(2):357–75. doi: 10.1016/j.bbamem.2007.11.008 WOS:000253269700001. 18078805

9. Afrasiabi Z, Almudhafar R, Xiao D, Sinn E, Choudhury A, Ahmad A, et al. Metal-based anticancer agents: targeting androgen-dependent and androgen-independent prostate and COX-positive pancreatic cancer cells by phenanthrenequinone semicarbazone and its metal complexes. Transit Metal Chem. 2013;38(6):665–73. doi: 10.1007/s11243-013-9735-3 WOS:000323104800009.

10. Hyun S, Lee S, Kim S, Jang S, Yu J, Lee Y. Apoptosis Inducing, Conformationally Constrained, Dimeric Peptide Analogs of KLA with Submicromolar Cell Penetrating Abilities. Biomacromolecules. 2014;15(10):3746–52. doi: 10.1021/bm501026e WOS:000343026600030. 25188534

11. Ellerby HM, Arap W, Ellerby LM, Kain R, Andrusiak R, Del Rio G, et al. Anti-cancer activity of targeted pro-apoptotic peptides. Nat Med. 1999;5(9):1032–8. WOS:000082337200037. doi: 10.1038/12469 10470080

12. Guo ZR, Li D, Peng HY, Kang JW, Jiang XY, Xie XL, et al. Specific hepatic stellate cell-penetrating peptide targeted delivery of a KLA peptide reduces collagen accumulation by inducing apoptosis. J Drug Target. 2017;25(8):715–23. doi: 10.1080/1061186X.2017.1322598 WOS:000404800400005. 28447897

13. Huang Y, Li XH, Sha HZ, Zhang LR, Bian XY, Han X, et al. Tumor-penetrating peptide fused to a pro-apoptotic peptide facilitates effective gastric cancer therapy. Oncol Rep. 2017;37(4):2063–70. doi: 10.3892/or.2017.5440 WOS:000398138900017. 28260064

14. Zhao LJ, Huang YB, Gao S, Cui Y, He D, Wang L, et al. Comparison on effect of hydrophobicity on the antibacterial and antifungal activities of alpha-helical antimicrobial peptides. Sci China Chem. 2013;56(9):1307–14. doi: 10.1007/s11426-013-4884-y WOS:000323505300024.

15. Zhao J, Huang YB, Liu D, Chen YX. Two hits are better than one: synergistic anticancer activity of α-helical peptides and doxorubicin/epirubicin. Oncotarget. 2015;6(3):1769–78. doi: 10.18632/oncotarget.2754 WOS:000352689800036. 25593197

16. Hao XY, Yan QY, Zhao J, Wang WR, Huang YB, Chen YX. TAT Modification of Alpha-Helical Anticancer Peptides to Improve Specificity and Efficacy. Plos One. 2015;10(9). ARTN e0138911 doi: 10.1371/journal.pone.0138911 WOS:000361800700117. 26405806

17. Chen Y, Mant CT, Hodges RS. Determination of stereochemistry stability coefficients of amino acid side-chains in an amphipathic alpha-helix. J Pept Res. 2002;59(1):18–33. doi: 10.1046/j.1397-002x.2001.10994.x WOS:000174259700003. 11906604

18. Chen YX, Vasil AI, Rehaume L, Mant CT, Burns JL, Vasil ML, et al. Comparison of biophysical and biologic properties of alpha-helical enantiomeric antimicrobial peptides. Chem Biol Drug Des. 2006;67(2):162–73. doi: 10.1111/j.1747-0285.2006.00349.x WOS:000236474300008. 16492164

19. Bartsch I, Willbold E, Yarmolenko S, Witte F. In vivo fluorescence imaging of apoptosis during foreign body response. Biomaterials. 2012;33(29):6926–32. doi: 10.1016/j.biomaterials.2012.06.039 22818983.

20. De GJ, Ko JK, Tan T, Zhu H, Li HC, Ma JJ. Amphipathic tail-anchoring peptide is a promising therapeutic agent for prostate cancer treatment. Oncotarget. 2014;5(17):7734–47. doi: 10.18632/oncotarget.2301 WOS:000348029800041. 25245280

21. Chen R, Braun GB, Luo X, Sugahara KN, Teesalu T, Ruoslahti E. Application of a proapoptotic peptide to intratumorally spreading cancer therapy. Cancer Res. 2013;73(4):1352–61. doi: 10.1158/0008-5472.CAN-12-1979 23248118; PubMed Central PMCID: PMC3578137.

22. Chobot V, Hadacek F, Kubicova L. Effects of selected dietary secondary metabolites on reactive oxygen species production caused by iron(II) autoxidation. Molecules. 2014;19(12):20023–33. doi: 10.3390/molecules191220023 25470272; PubMed Central PMCID: PMC4351905.

23. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 1999;397(6718):441–6. doi: 10.1038/17135 9989411.

24. Rudolf E, Cervinka M. The role of intracellular zinc in chromium(VI)-induced oxidative stress, DNA damage and apoptosis. Chem Biol Interact. 2006;162(3):212–27. doi: 10.1016/j.cbi.2006.06.005 16887109.

25. Cieslewicz M, Tang JJ, Yu JL, Cao H, Zavaljevski M, Motoyama K, et al. Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival. P Natl Acad Sci USA. 2013;110(40):15919–24. doi: 10.1073/pnas.1312197110 WOS:000325105500033. 24046373

26. Foillard S, Jin ZH, Garanger E, Boturyn D, Favrot MC, Coll JL, et al. Synthesis and Biological Characterisation of Targeted Pro-Apoptotic Peptide. Chembiochem. 2008;9(14):2326–32. doi: 10.1002/cbic.200800327 WOS:000260086000021. 18712748

27. Javadpour MM, Juban MM, Lo WC, Bishop SM, Alberty JB, Cowell SM, et al. De novo antimicrobial peptides with low mammalian cell toxicity. J Med Chem. 1996;39(16):3107–13. doi: 10.1021/jm9509410 8759631.

28. Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Greenwald DR, et al. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science. 2010;328(5981):1031–5. doi: 10.1126/science.1183057 20378772; PubMed Central PMCID: PMC2881692.

29. Mai XT, Huang J, Tan J, Huang Y, Chen Y. Effects and mechanisms of the secondary structure on the antimicrobial activity and specificity of antimicrobial peptides. J Pept Sci. 2015;21(7):561–8. doi: 10.1002/psc.2767 25826179.

30. Li H, Kolluri SK, Gu J, Dawson MI, Cao X, Hobbs PD, et al. Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science. 2000;289(5482):1159–64. doi: 10.1126/science.289.5482.1159 10947977.

Článek vyšel v časopise


2019 Číslo 11