Matrix metalloproteinase-activated anthrax lethal toxin demonstrates high potency in targeting tumor vasculature

Shihui Liu, Hailun Wang, Brooke M. Currie, Alfredo Molinolo, Howard J. Leung, Mahtab Moayeri, John R. Basile, Randall W. Alfano, J. Silvio Gutkind, Arthur E. Frankel, Thomas H. Bugge, Stephen H. Leppla

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Anthrax lethal toxin (LT), a virulence factor secreted by Bacillus anthracis, is selectively toxic to human melanomas with the BRAF V600E activating mutation because of its proteolytic activities toward the mitogen-activated protein kinase kinases (MEKs). To develop LT variants with lower in vivo toxicity and high tumor specificity, and therefore greater potential for clinical use, we generated a mutated LT that requires activation by matrix metalloproteinases (MMPs). This engineered toxin was less toxic than wild-type LT to mice because of the limited expression of MMPs by normal cells. Moreover, the systemically administered toxin produced greater anti-tumor effects than wild-type LT toward human xenografted tumors. This was shown to result from its greater bioavailability, a consequence of the limited uptake and clearance of the modified toxin by normal cells. Furthermore, the MMP-activated LT had very potent anti-tumor activity not only to human melanomas containing the BRAF mutation but also to other tumor types, including lung and colon carcinomas regardless of their BRAF status. Tumor histology and in vivo angiogenesis assays showed that this antitumor activity is due largely to the indirect targeting of tumor vasculature and angiogenic processes. Thus, even tumors genetically deficient in anthrax toxin receptors were still susceptible to the toxin therapy in vivo. Moreover, the modified toxin also displayed lower immunogenicity compared with the wild-type toxin. All these properties suggest that this MMP-activated antitumor toxin has potential for use in cancer therapy.

Original languageEnglish (US)
Pages (from-to)529-540
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number1
DOIs
StatePublished - Jan 4 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Liu, S., Wang, H., Currie, B. M., Molinolo, A., Leung, H. J., Moayeri, M., Basile, J. R., Alfano, R. W., Gutkind, J. S., Frankel, A. E., Bugge, T. H., & Leppla, S. H. (2008). Matrix metalloproteinase-activated anthrax lethal toxin demonstrates high potency in targeting tumor vasculature. Journal of Biological Chemistry, 283(1), 529-540. https://doi.org/10.1074/jbc.M707419200