Urokinase-targeted recombinant bacterial protein toxins – a rationally designed and engineered anticancer agent for cancer therapy

Abstract

Urokinase-targeted recombinant bacterial protein toxins are a sort of rationally designed and engineered anticancer recombinant fusion proteins representing a novel class of agents for cancer therapy. Bacterial protein toxins have long been known as the primary virulence factor(s) for a variety of pathogenic bacteria and are the most powerful human poisons. On the other hand, it has been well documented that urokinase-type plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR), making up the uPA system, are overexpressed in a variety of human tumors and tumor cell lines. The expression of uPA system is highly correlated with tumor invasion and metastasis. To exploit these characteristics in the design of tumor cell-selective cytotoxins, two prominent bacterial protein toxins, i.e., the diphtheria toxin and anthrax toxin are deliberately engineered through placing a sequence targeted specifically by the uPA system to form anticancer recombinant fusion proteins. These uPA system-targeted bacterial protein toxins are activated selectively on the surface of uPA system-expressing tumor cells, thereby killing these cells. This article provides a review on the latest progress in the exploitation of these recombinant fusion proteins as potent tumoricidal agents. It is perceptible that the strategies for cancer therapy are being innovated by this novel therapeutic approach.

Keywords

urokinase-type plasminogen activator (uPA) / diphtheria toxin, anthrax toxin / recombinant fusion proteins / cancer therapy

References

[1] Abi-HabibR J, LiuS H, BuggeT H, LepplaS H, FrankelA E (2004). A urokinase-activated recombinant diphtheria toxin targeting the granulocyte-macrophage colony-stimulating factor receptor is selectively cytotoxic to human acute myeloid leukemia blasts. Blood, 104: 2143–2148

[2] Abi-HabibR J, SinghR, LiuS, BuggeT H, LepplaS H, FrankelA E (2006). A urokinase-activated recombinant anthrax toxin is selectively cytotoxic to many human tumor cell types. Mol Cancer Ther, 5: 2556–2562

[3] AroraN, LepplaS H (1993). Residues 1–254 of anthrax toxin lethal factor are sufficient to cause cellular uptake of fused polypeptides. J Biol Chem, 268: 3334–3341

[4] ChoongP F, NadesapillaiA P (2003). Urokinase plasminogen activator system: a multifunctional role in tumor progression and metastasis. Clin Orthop Relat Res, 415(Suppl) S46–58

[5] DuffyM J (2004). The urokinase plasminogen activator system: role in malignancy. Curr Pharm Design, 10: 39–49

[6] DuffyM J, DugganC (2004). The urokinase plasminogen activator system: a rich source of tumour markers for the individualized management of patients with cancer. Clinical Biochemistry, 37: 541–548 Special Issue: Recent Advances in Cancer Biomarkers

[7] EhrlichP (1956). The relationship existing between chemical constitution, distribution, and pharmacologic action. In: Himmelweite F, Marquardt M, Dale H, ed. The Collected Papers of Paul Ehrlich, 1. London: Pergamon Press, 596–618

[8] FitzGeraldD J, KreitmanR, WilsonW, SquiresD, PastanI (2004). Recombinant immunotoxins for treating cancer. Int J Med Microbiol, 293: 577–582

[9] FrankelA E, BeranM, HoggeD E, PowellB L, ThorburnA, ChenY Q, ValleraD A (2002). Malignant progenitors from patients with CD87+ acute myelogenous leukemia are sensitive to a diphtheria toxin-urokinase fusion protein. Exp Hematol, 30: 1316–1323

[10] FrankelA E, RossiP, KuzelT M, FossF (2002). Diphtheria fusion protein therapy of chemoresistant malignancies. Curr Cancer Drug Targets, 2: 19–36

[11] HolmesR K (2000). Biology and molecular epidemiology of diphtheria toxin and the tox gene. J� Infect Dis, 181Suppl 1: S156–167

[12] KlimpelK R, MolloyS S, ThomasG, LepplaS H (1992). Anthrax toxin protective antigen is activated by a cell surface protease with the sequence specificity and catalytic properties of furin. Proc Natl Acad Sci USA, 89: 10277–10281

[13] LiuS, AaronsonH, MitolaD J, LepplaS H, BuggeT H (2003). Potent antitumor activity of a urokinase-activated engineered anthrax toxin. Proc Natl Acad Sci U S A, 100: 657–662

[14] LiuS, BuggeT H, LepplaS H (2001). Targeting of tumor cells by cell surface urokinase plasminogen activator-dependent anthrax toxin. J Biol Chem, 276: 17976–17984

[15] LiuS, RedeyeV, KuremskyJ G, KuhnenM, MolinoloA, BuggeT H, LepplaS H (2005). Intermolecular complementation achieves high-specificity tumor targeting by anthrax toxin. Nat Biotechnol, 23: 725–730

[16] LiuS, SchubertR L, BuggeT H, LepplaS H (2003). Anthrax toxin: structures, functions and tumour targeting. Expert Opin Biol Ther, 3: 843–853

[17] MogridgeJ, CunninghamK, CollierR J (2002). Stoichiometry of anthrax toxin complexes. Biochemistry, 41: 1079–1082

[18] MooltenF L, CapparellN J, ZajdelS H, CooperbandS R (1975). Antitumor Effects of Antibody-Diphtheria Toxin Conjugates. II. Immunotherapy with Conjugates Directed against Tumor Antigens Induced by Simian Virus 40.J Natl Cancer Inst, 55: 473–477

[19] RamageJ G, ValleraD A, BlackJ H, AplanP D, KeesU R, FrankelA E (2003). The diphtheria toxin/urokinase fusion protein (DTAT) is selectively toxic to CD87 expressing leukemic cells. Leuk Res, 27: 79–84

[20] RønøB, RømerJ, LiuS, BuggeT H, LepplaS H, KristjansenP E (2006). Antitumor efficacy of a urokinase activation-dependent anthrax toxin. Mol Cancer Ther, 5: 89–96

[21] RustamzadehE, HallW A, TodhunterD A, ValleraV D, LowW C, LiuH, Panoskaltsis-MortariA, ValleraD A (2006). Intracranial therapy of glioblastoma with the fusion protein DTAT in immunodeficient mice. Int J Cancer, 120: 411–419

[22] RustamzadehE, ValleraD A, TodhunterD A, LowW C, Panoskaltsis-MortariA, HallW A (2006). Immunotoxin pharmacokinetics: a comparison of the anti-glioblastoma bi-specific fusion protein (DTAT13) to DTAT and DTIL13. J Neurooncol, 77: 257–266

[23] SchlessingerD, SchaechterM (1993). Bacterial toxins. In: Schaechter M, Medoff G, Eisenstein B I, editors.Mechanisms of microbial disease. 2nd ed. Baltimore: Williams and Wilkins, 162–175

[24] SuY, OrtizJ, LiuS, BuggeT H, SinghR, LepplaS H, FrankelA E (2007). Systematic urokinase-activated anthrax toxin therapy produces regressions of subcutaneous human non-small cell lung tumor in athymic nude mice. Cancer Res, 67: 3329–3336

[25] TodarK (2008a). Bacterial Protein Toxins. In: Todar's Online Textbook of Bacteriology(http://www.textbookofbacteriology.net/proteintoxins.html)

[26] TodarK (2008b). Diphtheria. In: Todar's Online Textbook of Bacteriology(http://www.textbookofbacteriology.net/diphtheria.html)

[27] TodarK (2008c). Pseudomonas aeruginosa. In: Todar's Online Textbook of Bacteriology (http://www.textbookofbacteriology.net/pseudomonas.html)

[28] TodarK (2008d). Bacillus anthracis and anthrax. In: Todar's Online Textbook of Bacteriology(http://www.textbookofbacteriology.net/Anthrax.html)

[29] TodhunterD A, HallW A, RustamzadehE, ShuY, DoumbiaS O, ValleraD A (2004). A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model. Protein Eng Des Sel, 17: 157–164

[30] ValleraD A, LiC, JinN, Panoskaltsis-MortariA, HallW A (2002). Targeting urokinase-type plasminogen activator receptor on human glioblastoma tumors with diphtheria toxin fusion protein DTAT. J Natl Cancer Inst, 94: 597–606

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg