International Journal of Cancer Management

Published by: Kowsar

In Silico Evaluation of Two Targeted Chimeric Proteins Based on Bacterial Toxins for Breast Cancer Therapy

Zoleikha Goleij 1 , Hamideh Mahmoodzadeh Hosseini 1 , ** , Mohsen Amin 2 , Jafar Amani 1 , Elham Behzadi 3 and Abbas Ali Imani Fooladi 1 , *
Authors Information
1 Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
2 Department of Drug and Food Control, Faculty of Pharmacy and the Institute Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran, Iran
3 Department of Microbiology, College of Basic Sciences, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran
Corresponding Authors:
Article information
  • International Journal of Cancer Management: February 28, 2019, 12 (2); e83315
  • Published Online: February 5, 2019
  • Article Type: Research Article
  • Received: August 14, 2018
  • Revised: January 16, 2019
  • Accepted: January 16, 2019
  • DOI: 10.5812/ijcm.83315

To Cite: Goleij Z , Mahmoodzadeh Hosseini H , Amin M , Amani J , Behzadi E, et al. In Silico Evaluation of Two Targeted Chimeric Proteins Based on Bacterial Toxins for Breast Cancer Therapy, Int J Cancer Manag. 2019 ; 12(2):e83315. doi: 10.5812/ijcm.83315.

Copyright © 2019, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
1. Background
2. Methods
3. Results
4. Discussion
  • 1. Li SG, Li L. Targeted therapy in HER2-positive breast cancer. Biomed Rep. 2013;1(4):499-505. doi: 10.3892/br.2013.95. [PubMed: 24648975]. [PubMed Central: PMC3917005].
  • 2. Ross JS, Fletcher JA, Bloom KJ, Linette GP, Stec J, Symmans WF, et al. Targeted therapy in breast cancer: The HER-2/neu gene and protein. Mol Cell Proteomics. 2004;3(4):379-98. doi: 10.1074/mcp.R400001-MCP200. [PubMed: 14762215].
  • 3. Schechter AL, Stern DF, Vaidyanathan L, Decker SJ, Drebin JA, Greene MI, et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984;312(5994):513-6. [PubMed: 6095109].
  • 4. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127-37. doi: 10.1038/35052073. [PubMed: 11252954].
  • 5. Becker N, Benhar I. Antibody-based immunotoxins for the treatment of cancer. Antibodies. 2012;1(1):39-69. doi: 10.3390/antib1010039.
  • 6. Reichert JM. Antibody-based therapeutics to watch in 2011. MAbs. 2011;3(1):76-99. [PubMed: 21051951]. [PubMed Central: PMC3038014].
  • 7. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: A german breast group 26/breast international group 03-05 study. J Clin Oncol. 2009;27(12):1999-2006. doi: 10.1200/JCO.2008.19.6618. [PubMed: 19289619].
  • 8. Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: Results from the randomized phase III TAnDEM study. J Clin Oncol. 2009;27(33):5529-37. doi: 10.1200/JCO.2008.20.6847. [PubMed: 19786670].
  • 9. Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J. Trastuzumab (Herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 2001;61(12):4744-9. [PubMed: 11406546].
  • 10. Nahta R, Esteva FJ. HER2 therapy: Molecular mechanisms of trastuzumab resistance. Breast Cancer Res. 2006;8(6):215. doi: 10.1186/bcr1612. [PubMed: 17096862]. [PubMed Central: PMC1797036].
  • 11. Dosio F, Brusa P, Cattel L. Immunotoxins and anticancer drug conjugate assemblies: The role of the linkage between components. Toxins (Basel). 2011;3(7):848-83. doi: 10.3390/toxins3070848. [PubMed: 22069744]. [PubMed Central: PMC3202854].
  • 12. Kreitman RJ, Hassan R, Fitzgerald DJ, Pastan I. Phase I trial of continuous infusion anti-mesothelin recombinant immunotoxin SS1P. Clin Cancer Res. 2009;15(16):5274-9. doi: 10.1158/1078-0432.CCR-09-0062. [PubMed: 19671873]. [PubMed Central: PMC2754261].
  • 13. Allured VS, Collier RJ, Carroll SF, McKay DB. Structure of exotoxin A of Pseudomonas aeruginosa at 3.0-Angstrom resolution. Proc Natl Acad Sci U S A. 1986;83(5):1320-4. doi: 10.1073/pnas.83.5.1320. [PubMed: 3006045]. [PubMed Central: PMC323067].
  • 14. Hwang J, Fitzgerald DJ, Adhya S, Pastan I. Functional domains of Pseudomonas exotoxin identified by deletion analysis of the gene expressed in E. coli. Cell. 1987;48(1):129-36. doi: 10.1016/0092-8674(87)90363-1. [PubMed: 3098436].
  • 15. Siegall CB, Chaudhary VK, FitzGerald DJ, Pastan I. Functional analysis of domains II, Ib, and III of Pseudomonas exotoxin. J Biol Chem. 1989;264(24):14256-61. [PubMed: 2503515].
  • 16. Kihara A, Pastan I. Analysis of sequences required for the cytotoxic action of a chimeric toxin composed of Pseudomonas exotoxin and transforming growth factor alpha. Bioconjug Chem. 1994;5(6):532-8. doi: 10.1021/bc00030a008. [PubMed: 7873657].
  • 17. Fraser ME, Chernaia MM, Kozlov YV, James MN. Crystal structure of the holotoxin from Shigella dysenteriae at 2.5 A resolution. Nat Struct Biol. 1994;1(1):59-64. doi: 10.1038/nsb0194-59. [PubMed: 7656009].
  • 18. Jacewicz M, Clausen H, Nudelman E, Donohue-Rolfe A, Keusch GT. Pathogenesis of shigella diarrhea. XI. Isolation of a shigella toxin-binding glycolipid from rabbit jejunum and HeLa cells and its identification as globotriaosylceramide. J Exp Med. 1986;163(6):1391-404. doi: 10.1084/jem.163.6.1391. [PubMed: 3519828]. [PubMed Central: PMC2188132].
  • 19. Garred O, Dubinina E, Polesskaya A, Olsnes S, Kozlov J, Sandvig K. Role of the disulfide bond in Shiga toxin A-chain for toxin entry into cells. J Biol Chem. 1997;272(17):11414-9. doi: 10.1074/jbc.272.17.11414. [PubMed: 9111051].
  • 20. O'Brien AD, Tesh VL, Donohue-Rolfe A, Jackson MP, Olsnes S, Sandvig K, et al. Shiga toxin: Biochemistry, genetics, mode of action, and role in pathogenesis. Curr Top Microbiol Immunol. 1992;180:65-94. [PubMed: 1324134].
  • 21. Fuller CA, Pellino CA, Flagler MJ, Strasser JE, Weiss AA. Shiga toxin subtypes display dramatic differences in potency. Infect Immun. 2011;79(3):1329-37. doi: 10.1128/IAI.01182-10. [PubMed: 21199911]. [PubMed Central: PMC3067513].
  • 22. Grupka NL, Lear-Kaul KC, Kleinschmidt-DeMasters BK, Singh M. Epidermal growth factor receptor status in breast cancer metastases to the central nervous system. Comparison with HER-2/neu status. Arch Pathol Lab Med. 2004;128(9):974-9. doi: 10.1043/1543-2165(2004)128<974:EGFRSI>2.0.CO;2. [PubMed: 15335267].
  • 23. Aziz SA, Pervez S, Khan S, Kayani N, Rahbar MH. Epidermal growth factor receptor (EGFR) as a prognostic marker: An immunohistochemical study on 315 consecutive breast carcinoma patients. J Pak Med Assoc. 2002;52(3):104-10. [PubMed: 12071064].
  • 24. Baloria U, Akhoon BA, Gupta SK, Sharma S, Verma V. In silico proteomic characterization of human epidermal growth factor receptor 2 (HER-2) for the mapping of high affinity antigenic determinants against breast cancer. Amino Acids. 2012;42(4):1349-60. doi: 10.1007/s00726-010-0830-x. [PubMed: 21229277].
  • 25. Ghasemi A, Ranjbar R, Amani J. In silico analysis of chimeric TF, Omp31 and BP26 fragments of Brucella melitensis for development of a multi subunit vaccine candidate. Iran J Basic Med Sci. 2014;17(3):172-80. [PubMed: 24847419]. [PubMed Central: PMC4016687].
  • 26. Amala S. In silico analysis and 3D modeling of ASAH1 protein in farber lipogranulomatosis. Adv Biotech. 2010;10(6):6-8.
  • 27. Garnier J, Gibrat JF, Robson B. GOR method for predicting protein secondary structure from amino acid sequence. Methods Enzymol. 1996;266:540-53. doi: 10.1016/S0076-6879(96)66034-0. [PubMed: 8743705].
  • 28. Zhang Y. I-TASSER server for protein 3D structure prediction. BMC Bioinformatics. 2008;9:40. doi: 10.1186/1471-2105-9-40. [PubMed: 18215316]. [PubMed Central: PMC2245901].
  • 29. Guex N, Peitsch MC. SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling. Electrophoresis. 1997;18(15):2714-23. doi: 10.1002/elps.1150181505. [PubMed: 9504803].
  • 30. Ahmad S, Gromiha M, Fawareh H, Sarai A. ASAView: Database and tool for solvent accessibility representation in proteins. BMC Bioinformatics. 2004;5:51. doi: 10.1186/1471-2105-5-51. [PubMed: 15119964]. [PubMed Central: PMC420234].
  • 31. Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK: A program to check the stereochemical quality of protein structures. J Appl Crystallogr. 1993;26(2):283-91. doi: 10.1107/s0021889892009944.
  • 32. Mahboobi M, Sedighian H, Hedayati Ch M, Bambai B, Esmaeil Soofian S, Amani J. Applying bioinformatic tools for modeling and modifying type ii e. Coli l-asparginase to present a better therapeutic agent/drug for acute lymphoblastic leukemia. Int J Cancer Manag. 2017;10(3). doi: 10.5812/ijcm.5785.
  • 33. Kovtun YV, Goldmacher VS. Cell killing by antibody-drug conjugates. Cancer Lett. 2007;255(2):232-40. doi: 10.1016/j.canlet.2007.04.010. [PubMed: 17553616].
  • 34. Junutula JR, Raab H, Clark S, Bhakta S, Leipold DD, Weir S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26(8):925-32. doi: 10.1038/nbt.1480. [PubMed: 18641636].
  • 35. Jiang H, Rugo HS. Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer: How the latest results are improving therapeutic options. Ther Adv Med Oncol. 2015;7(6):321-39. doi: 10.1177/1758834015599389. [PubMed: 26557900]. [PubMed Central: PMC4622301].
  • 36. Ahmad ZA, Yeap SK, Ali AM, Ho WY, Alitheen NB, Hamid M. scFv antibody: Principles and clinical application. Clin Dev Immunol. 2012;2012:980250. doi: 10.1155/2012/980250. [PubMed: 22474489]. [PubMed Central: PMC3312285].
  • 37. Keshtvarz M, Salimian J, Yaseri M, Bathaie SZ, Rezaie E, Aliramezani A, et al. Bioinformatic prediction and experimental validation of a PE38-based recombinant immunotoxin targeting the Fn14 receptor in cancer cells. Immunotherapy. 2017;9(5):387-400. doi: 10.2217/imt-2017-0008. [PubMed: 28357912].
  • 38. Imani-Fooladi AA, Yousefi F, Mousavi SF, Amani J. In silico design and analysis of TGFalphaL3-SEB fusion protein as "a new antitumor agent" candidate by ligand-targeted superantigens technique. Iran J Cancer Prev. 2014;7(3):152-64. [PubMed: 25250167]. [PubMed Central: PMC4171824].
  • 39. Chen X, Zaro JL, Shen WC. Fusion protein linkers: Property, design and functionality. Adv Drug Deliv Rev. 2013;65(10):1357-69. doi: 10.1016/j.addr.2012.09.039. [PubMed: 23026637]. [PubMed Central: PMC3726540].

Featured Image:

Creative Commons License Except where otherwise noted, this work is licensed under Creative Commons Attribution Non Commercial 4.0 International License .

Search Relations:



Create Citiation Alert
via Google Reader

Readers' Comments