Login Register Cart 0
Generic placeholder image

Current Bioactive Compounds

Editor-in-Chief

ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Cationicity and Hydrophobicity Enhance the Cytotoxic Potency of Phoratoxin C Anticancer Peptide Analogues against Triple Negative Breast Cancer Cells

Author(s): Chu Xin Ng, Cheng Foh Le and Sau Har Lee*

Volume 17, Issue 9, 2021

Published on: 12 January, 2021

Article ID: e040821190233 Pages: 12

DOI: 10.2174/1573407217999210112180404

Price: $65

Abstract

Background: Anticancer Peptides (ACPs) have received increasing attention as a promising class of novel anticancer agents owing to their potent and rapid cytotoxic properties. In this study, we aim to investigate the effects of cationicity and hydrophobicity in modulating the cytotoxicity of PtxC, a class of ACP from the leafy mistletoe Phoradendron tomentosum against the MDA-MB-231 and Vero cells.

Methods: We designed a series of four PtxC analogues (PA1 – PA4) by residual substitutions with specific amino acids to introduce the specific charge and hydrophobicity alterations to the analogues. The cytotoxicity strength of the PtxC analogues on MDA-MB-231 and Vero cells was tested using MTT assay 24 hours post-treatment.

Results: PA1, PA2, and PA4 displayed marked increases in cytotoxicity against both MDA-MB- 231 and Vero cells and can be ranked in the order of PA2 > PA4 > PA1 > PtxC > PA3. Sequence- activity relationship analyses of the designed analogues showed that an increase in the level of cationicity and hydrophobicity correlated well with the enhanced cytotoxic activity of PtxC analogues. This was observed with PA1 (netC +8) and PA2 (netC +10) in comparison to PtxC (netC +7). A similar finding was observed for PA4 (GRAVY +0.070) in contrast to PtxC (GRAVY -0.339). Three-dimensional modelling predicted a double α-helix structure in PtxC class of ACP. The larger first helix in PA2 and PA4 was suggested to be responsible for the enhanced cytotoxicity observed.

Conclusion: The critical role of cationicity and hydrophobicity in enhancing cytotoxicity of PtxC class of ACPs was clearly demonstrated in our study. The current findings could be extrapolated to benefit peptide design strategy in other classes of ACPs toward the discovery of highly potent ACPs against cancer cells as potential novel therapeutic agents.

Keywords: Anticancer activity, chemotherapy, hybrid peptide, linear peptide, MDA-MB-231, hydrophobicity.

Graphical Abstract

[1]
Kalinowski, L.; Saunus, J.M.; McCart Reed, A.E.; Lakhani, S.R. Breast cancer heterogeneity in primary and metastatic disease.Advances in Experimental Medicine and Biology; Springer New York LLC, 2019, Vol. 1152, pp. 75-104.
[2]
Shao, F.; Sun, H.; Deng, C-X. Potential therapeutic targets of triple-negative breast cancer based on its intrinsic subtype. Oncotarget, 2017, 8(42), 73329-73344.
[http://dx.doi.org/10.18632/oncotarget.20274] [PMID: 29069872]
[3]
Cejalvo, J.M.; Martínez de Dueñas, E.; Galván, P.; García-Recio, S.; Burgués Gasión, O.; Paré, L.; Antolín, S.; Martinello, R.; Blancas, I.; Adamo, B.; Guerrero-Zotano, Á.; Muñoz, M.; Nucíforo, P.; Vidal, M.; Pérez, R.M.; Chacón López-Muniz, J.I.; Caballero, R.; Peg, V.; Carrasco, E.; Rojo, F.; Perou, C.M.; Cortés, J.; Adamo, V.; Albanell, J.; Gomis, R.R.; Lluch, A.; Prat, A. Intrinsic subtypes and gene expression profiles in primary and metastatic breast cancer. Cancer Res., 2017, 77(9), 2213-2221.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-2717] [PMID: 28249905]
[4]
Garrido-Castro, A. C.; Lin, N. U.; Polyak, K. Insights into molecular classifications of triple-negative breast cancer: Improving patient selection for treatment.Cancer Discovery; American Association for Cancer Research Inc., 2019, pp. 176-198.
[5]
Tao, J.J.; Visvanathan, K.; Wolff, A.C. Long term side effects of adjuvant chemotherapy in patients with early breast cancer. Breast, 2015, 24(Suppl. 2), S149-S153.
[http://dx.doi.org/10.1016/j.breast.2015.07.035] [PMID: 26299406]
[6]
Fitzmaurice, C.; Allen, C.; Barber, R. M.; Barregard, L.; Bhutta, Z. A.; Brenner, H.; Dicker, D. J.; Chimed-Orchir, O.; Dandona, R.; Dandona, L. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the global burden of disease study global burden of disease cancer collaboration. JAMA Oncology., 1990, , 524-548.
[7]
Al-Mahmood, S.; Sapiezynski, J.; Garbuzenko, O. B.; Minko, T. Metastatic and Triple-Negative Breast Cancer: Challenges and Treatment Options. Drug Delivery and Translational Research., 2018, , 1483-1507.
[8]
Johansson, S.; Gullbo, J.; Lindholm, P.; Ek, B.; Thunberg, E.; Samuelsson, G.; Larsson, R.; Bohlin, L.; Claeson, P. Small, novel proteins from the mistletoe Phoradendron tomentosum exhibit highly selective cytotoxicity to human breast cancer cells. Cell. Mol. Life Sci., 2003, 60(1), 165-175.
[http://dx.doi.org/10.1007/s000180300011] [PMID: 12613665]
[9]
Ireland, D.C.; Colgrave, M.L.; Craik, D.J. A novel suite of cyclotides from Viola odorata: sequence variation and the implications for structure, function and stability. Biochem. J., 2006, 400(1), 1-12.
[http://dx.doi.org/10.1042/BJ20060627] [PMID: 16872274]
[10]
Svangård, E.; Burman, R.; Gunasekera, S.; Lövborg, H.; Gullbo, J.; Göransson, U. Mechanism of action of cytotoxic cyclotides: cycloviolacin O2 disrupts lipid membranes. J. Nat. Prod., 2007, 70(4), 643-647.
[http://dx.doi.org/10.1021/np070007v] [PMID: 17378610]
[11]
Burman, R.; Svedlund, E.; Felth, J.; Hassan, S.; Herrmann, A.; Clark, R.J.; Craik, D.J.; Bohlin, L.; Claeson, P.; Göransson, U.; Gullbo, J. Evaluation of toxicity and antitumor activity of cycloviolacin O2 in mice. Biopolymers, 2010, 94(5), 626-634.
[http://dx.doi.org/10.1002/bip.21408] [PMID: 20564012]
[12]
Philippe, G.J.B.; Gaspar, D.; Sheng, C.; Huang, Y.H.; Benfield, A.H.; Condon, N.D.; Weidmann, J.; Lawrence, N.; Löwer, A.; Castanho, M.A.R.B.; Craik, D.J.; Troeira Henriques, S. Cell membrane composition drives selectivity and toxicity of designed cyclic helix-loop-helix peptides with cell penetrating and yumor suppressor properties. ACS Chem. Biol., 2019, 14(9), 2071-2087.
[http://dx.doi.org/10.1021/acschembio.9b00593] [PMID: 31390185]
[13]
Lee, C-S.; Taib, N.A.M.; Ashrafzadeh, A.; Fadzli, F.; Harun, F.; Rahmat, K.; Hoong, S.M.; Abdul-Rahman, P.S.; Hashim, O.H. Unmasking Heavily O-Glycosylated Serum Proteins Using Perchloric Acid: Identification of Serum Proteoglycan 4 and Protease C1 Inhibitor as Molecular Indicators for Screening of Breast Cancer. PLoS One, 2016, 11(2), e0149551.
[http://dx.doi.org/10.1371/journal.pone.0149551] [PMID: 26890881]
[14]
Segawa, K.; Nagata, S. An Apoptotic ‘Eat Me’ Signal: Phosphatidylserine Exposure. Trends Cell Biol., 2015, 25(11), 639-650.
[http://dx.doi.org/10.1016/j.tcb.2015.08.003] [PMID: 26437594]
[15]
Marien, E.; Meister, M.; Muley, T.; Fieuws, S.; Bordel, S.; Derua, R.; Spraggins, J.; Van de Plas, R.; Dehairs, J.; Wouters, J.; Bagadi, M.; Dienemann, H.; Thomas, M.; Schnabel, P.A.; Caprioli, R.M.; Waelkens, E.; Swinnen, J.V. Non-small cell lung cancer is characterized by dramatic changes in phospholipid profiles. Int. J. Cancer, 2015, 137(7), 1539-1548.
[http://dx.doi.org/10.1002/ijc.29517] [PMID: 25784292]
[16]
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(3), 416-426.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0811] [PMID: 21252288]
[17]
Lee, M.O.; Jang, H.J.; Rengaraj, D.; Yang, S.Y.; Han, J.Y.; Lamont, S.J.; Womack, J.E. Tissue expression and antibacterial activity of host defense peptides in chicken. BMC Vet. Res., 2016, 12(1), 231.
[http://dx.doi.org/10.1186/s12917-016-0866-6] [PMID: 27737668]
[18]
Lei, J.; Sun, L. C.; Huang, S.; Zhu, C.; Li, P.; He, J.; Mackey, V.; Coy, D. H.; He, Q. Y. The Antimicrobial Peptides and Their Potential Clinical Applications. American Journal of Translational Research., 2019, , 3919-3931.
[19]
Le, C.F.; Yusof, M.Y.M.; Hassan, H.; Sekaran, S.D. In vitro properties of designed antimicrobial peptides that exhibit potent antipneumococcal activity and produces synergism in combination with penicillin. Sci. Rep., 2015, 5, 9761.
[http://dx.doi.org/10.1038/srep09761] [PMID: 25985150]
[20]
Jindal, H.M.; Le, C.F.; Mohd Yusof, M.Y.; Velayuthan, R.D.; Lee, V.S.; Zain, S.M.; Isa, D.M.; Sekaran, S.D. Antimicrobial Activity of Novel Synthetic Peptides Derived from Indolicidin and Ranalexin against Streptococcus pneumoniae. PLoS One, 2015, 10(6), e0128532.
[http://dx.doi.org/10.1371/journal.pone.0128532] [PMID: 26046345]
[21]
Xue, X.; Liang, X.J. Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology. Chin. J. Cancer, 2012, 31(2), 100-109.
[http://dx.doi.org/10.5732/cjc.011.10326] [PMID: 22237039]
[22]
Zhang, J.; Liu, D.; Zhang, M.; Sun, Y.; Zhang, X.; Guan, G.; Zhao, X.; Qiao, M.; Chen, D.; Hu, H. The cellular uptake mechanism, intracellular transportation, and exocytosis of polyamidoamine dendrimers in multidrug-resistant breast cancer cells. Int. J. Nanomedicine, 2016, 11, 3677-3690.
[http://dx.doi.org/10.2147/IJN.S106418] [PMID: 27536106]
[23]
Lum, K.Y.; Tay, S.T.; Le, C.F.; Lee, V.S.; Sabri, N.H.; Velayuthan, R.D.; Hassan, H.; Sekaran, S.D. Activity of Novel Synthetic Peptides against Candida albicans. Sci. Rep., 2015, 5, 9657.
[http://dx.doi.org/10.1038/srep09657] [PMID: 25965506]
[24]
Leuschner, C.; Hansel, W. Membrane disrupting lytic peptides for cancer treatments. Curr. Pharm. Des., 2004, 10(19), 2299-2310.
[http://dx.doi.org/10.2174/1381612043383971] [PMID: 15279610]
[25]
Badana, A.; Chintala, M.; Varikuti, G.; Pudi, N.; Kumari, S.; Kappala, V.R.; Malla, R.R. Lipid Raft Integrity Is Required for Survival of Triple Negative Breast Cancer Cells. J. Breast Cancer, 2016, 19(4), 372-384.
[http://dx.doi.org/10.4048/jbc.2016.19.4.372] [PMID: 28053625]
[26]
Li, Y.C.; Park, M.J.; Ye, S.K.; Kim, C.W.; Kim, Y.N. Elevated levels of cholesterol-rich lipid rafts in cancer cells are correlated with apoptosis sensitivity induced by cholesterol-depleting agents. Am. J. Pathol., 2006, 168(4), 1107-1118.
[http://dx.doi.org/10.2353/ajpath.2006.050959] [PMID: 16565487]
[27]
Deslouches, B.; Di, Y.P. Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications. Oncotarget, 2017, 8(28), 46635-46651.
[http://dx.doi.org/10.18632/oncotarget.16743] [PMID: 28422728]
[28]
Du, Q.; Hou, X.; Ge, L.; Li, R.; Zhou, M.; Wang, H.; Wang, L.; Wei, M.; Chen, T.; Shaw, C. Cationicity-enhanced analogues of the antimicrobial peptides, AcrAP1 and AcrAP2, from the venom of the scorpion, Androctonus crassicauda, display potent growth modulation effects on human cancer cell lines. Int. J. Biol. Sci., 2014, 10(10), 1097-1107.
[http://dx.doi.org/10.7150/ijbs.9859] [PMID: 25332684]
[29]
Kawamoto, S.; Takasu, M.; Miyakawa, T.; Morikawa, R.; Oda, T.; Futaki, S.; Nagao, H. Inverted micelle formation of cell-penetrating peptide studied by coarse-grained simulation: importance of attractive force between cell-penetrating peptides and lipid head group. J. Chem. Phys., 2011, 134(9), 095103.
[http://dx.doi.org/10.1063/1.3555531] [PMID: 21385001]
[30]
Tuerkova, A.; Kabelka, I. Effect of Helical Kink in Antimicrobial Peptides on Membrane Pore Formation.
[31]
Theansungnoen, T.; Maijaroen, S.; Jangpromma, N.; Yaraksa, N.; Daduang, S.; Temsiripong, T.; Daduang, J.; Klaynongsruang, S. Cationic Antimicrobial Peptides Derived from Crocodylus siamensis Leukocyte Extract, Revealing Anticancer Activity and Apoptotic Induction on Human Cervical Cancer Cells. Protein J., 2016, 35(3), 202-211.
[http://dx.doi.org/10.1007/s10930-016-9662-1] [PMID: 27129462]
[32]
Haug, B.E.; Camilio, K.A.; Eliassen, L.T.; Stensen, W.; Svendsen, J.S.; Berg, K.; Mortensen, B.; Serin, G.; Mirjolet, J.F.; Bichat, F.; Rekdal, Ø. Discovery of a 9-mer Cationic Peptide (LTX-315) as a Potential First in Class Oncolytic Peptide. J. Med. Chem., 2016, 59(7), 2918-2927.
[http://dx.doi.org/10.1021/acs.jmedchem.5b02025] [PMID: 26982623]
[33]
Le, C.F.; Yusof, M.Y.M.; Hassan, M.A.A.; Lee, V.S.; Isa, D.M.; Sekaran, S.D. In vivo efficacy and molecular docking of designed peptide that exhibits potent antipneumococcal activity and synergises in combination with penicillin. Sci. Rep., 2015, 5, 11886.
[http://dx.doi.org/10.1038/srep11886] [PMID: 26156658]
[34]
Huang, Y.; Feng, Q.; Yan, Q.; Hao, X.; Chen, Y. Alpha-Helical Cationic Anticancer Peptides: A Promising Candidate for Novel Anticancer Drugs. 2015.
[http://dx.doi.org/10.2174/1389557514666141107120954]
[35]
Liu, X.; Cao, R.; Wang, S.; Jia, J.; Fei, H. Amphipathicity Determines Different Cytotoxic Mechanisms of Lysine- or Arginine-Rich Cationic Hydrophobic Peptides in Cancer Cells. J. Med. Chem., 2016, 59(11), 5238-5247.
[http://dx.doi.org/10.1021/acs.jmedchem.5b02016] [PMID: 27195657]
[36]
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(9), 1601-1610.
[http://dx.doi.org/10.1007/s00726-017-2453-y] [PMID: 28664269]
[37]
Cutrona, K.J.; Kaufman, B.A.; Figueroa, D.M.; Elmore, D.E. Role of arginine and lysine in the antimicrobial mechanism of histone-derived antimicrobial peptides. FEBS Lett., 2015, 589(24 Pt B), 3915-3920.
[http://dx.doi.org/10.1016/j.febslet.2015.11.002] [PMID: 26555191]
[38]
Zhang, Y.; Li, L.; Chang, L.; Liu, H.; Song, J.; Liu, Y.; Bao, H.; Liu, B.; Wang, R.; Ni, J. Design of a new pH-activatable cell-penetrating peptide for drug delivery into tumor cells. Chem. Biol. Drug Des., 2019, 94(5), 1884-1893.
[http://dx.doi.org/10.1111/cbdd.13537] [PMID: 31062442]
[39]
Jiang, T.; Zhang, Z.; Zhang, Y.; Lv, H.; Zhou, J.; Li, C.; Hou, L.; Zhang, Q. Dual-functional liposomes based on pH-responsive cell-penetrating peptide and hyaluronic acid for tumor-targeted anticancer drug delivery. Biomaterials, 2012, 33(36), 9246-9258.
[http://dx.doi.org/10.1016/j.biomaterials.2012.09.027] [PMID: 23031530]
[40]
Sang, M.; Zhang, J.; Zhuge, Q. Selective cytotoxicity of the antibacterial peptide ABP-dHC-Cecropin A and its analog towards leukemia cells. Eur. J. Pharmacol., 2017, 803, 138-147.
[http://dx.doi.org/10.1016/j.ejphar.2017.03.054] [PMID: 28347740]
[41]
Zhang, H.; Han, D.; Lv, T.; Liu, K.; Yang, Y.; Xu, X.; Chen, Y. Novel peptide myristoly-CM4 induces selective cytotoxicity in leukemia K562/MDR and Jurkat cells by necrosis and/or apoptosis pathway. Drug Des. Devel. Ther., 2019, 13, 2153-2167.
[http://dx.doi.org/10.2147/DDDT.S207224] [PMID: 31308628]
[42]
Chen, C.; Yang, C.; Chen, Y.; Wang, F.; Mu, Q.; Zhang, J.; Li, Z.; Pan, F.; Xu, H.; Lu, J.R. Surface Physical Activity and Hydrophobicity of Designed Helical Peptide Amphiphiles Control Their Bioactivity and Cell Selectivity. ACS Appl. Mater. Interfaces, 2016, 8(40), 26501-26510.
[http://dx.doi.org/10.1021/acsami.6b08297] [PMID: 27644109]
[43]
Dutt Sharma, R.; Jain, J.; Khosa, R.L. Short Chain Linear and Cyclic Cationic Peptide Designed from Cecropin B: Synthesis and Anticancer Activity. J. Appl. Pharm. Sci., 2019, 9(08), 1-010.
[http://dx.doi.org/10.7324/JAPS.2019.90801]
[44]
Yin, L.M.; Edwards, M.A.; Li, J.; Yip, C.M.; Deber, C.M. Roles of hydrophobicity and charge distribution of cationic antimicrobial peptides in peptide-membrane interactions. J. Biol. Chem., 2012, 287(10), 7738-7745.
[http://dx.doi.org/10.1074/jbc.M111.303602] [PMID: 22253439]
[45]
Tan, Y.; Chen, X.; Ma, C.; Xi, X.; Wang, L.; Zhou, M.; Burrows, J.F.; Kwok, H.F.; Chen, T. Biological Activities of Cationicity-Enhanced and Hydrophobicity-Optimized Analogues of an Antimicrobial Peptide, Dermaseptin-PS3, from the Skin Secretion of Phyllomedusa sauvagii. Toxins (Basel), 2018, 10(8), 320.
[http://dx.doi.org/10.3390/toxins10080320] [PMID: 30087268]

Rights & Permissions Print Cite
Article Metrics
16
2
© 2024 Bentham Science Publishers | Privacy Policy