Potent inhibition of tumor angiogenesis by the matrix metalloproteinase- activated anthrax lethal toxin

Implications for broad anti-tumor efficacy

Randall W. Alfano, Stephen H. Leppla, Shihui Liu, Thomas H. Bugge, Nicholas S. Duesbery, Arthur E. Frankel

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Angiogenesis is a critical step in solid tumor progression. The mitogen-activated protein kinase (MAPK) signaling pathways are central to this process, and thus present attractive targets for angiogenesis inhibition. Anthrax Lethal Toxin (LeTx), secreted from the gram positive Bacillus anthracis, demonstrates potent MAPK pathway inhibition. In vivo efficacy studies revealed that LeTx has broad anti-tumor efficacy via the targeting of angiogenesis. However, specificity in animal models was limited due to the presence of receptors on many normal tissues and the ubiquitous expression of furin in tissues. Further, half-life of LeTx was short due to circulating furin-like proteases. Gelatinases are expressed on tumor angiogenic sprouts and only to a limited extent in normal tissues or blood. In order to circumvent nonspecific LeTx activation, enhance tumor vascular targeting, and improve plasma half-life, a substrate preferably cleaved by gelatinases was substituted for the furin LeTx activation site. The MMP-activated LeTx showed potent angiogenic inhibition in vivo in the absence of systemic toxicity. Based on these studies, this attenuated toxin has clinical potential as a broad anti-tumor agent.

Original languageEnglish (US)
Pages (from-to)745-749
Number of pages5
JournalCell Cycle
Volume7
Issue number6
StatePublished - Mar 15 2008

Fingerprint

Matrix Metalloproteinases
Tumors
Furin
Gelatinases
Neoplasms
Tissue
Mitogen-Activated Protein Kinases
Half-Life
Chemical activation
Bacillus anthracis
Bacilli
Blood Vessels
Toxicity
Animals
Blood
Peptide Hydrolases
Animal Models
anthrax toxin
Plasmas
Substrates

Keywords

  • Angiogenesis
  • Anthrax lethal toxin
  • B-RAF
  • Lethal factor
  • Matrix metalloproteinase
  • Protective antigen

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Cite this

Potent inhibition of tumor angiogenesis by the matrix metalloproteinase- activated anthrax lethal toxin : Implications for broad anti-tumor efficacy. / Alfano, Randall W.; Leppla, Stephen H.; Liu, Shihui; Bugge, Thomas H.; Duesbery, Nicholas S.; Frankel, Arthur E.

In: Cell Cycle, Vol. 7, No. 6, 15.03.2008, p. 745-749.

Research output: Contribution to journalArticle

Alfano, Randall W. ; Leppla, Stephen H. ; Liu, Shihui ; Bugge, Thomas H. ; Duesbery, Nicholas S. ; Frankel, Arthur E. / Potent inhibition of tumor angiogenesis by the matrix metalloproteinase- activated anthrax lethal toxin : Implications for broad anti-tumor efficacy. In: Cell Cycle. 2008 ; Vol. 7, No. 6. pp. 745-749.
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