A urokinase-activated recombinant anthrax toxin is selectively cytotoxic to many human tumor cell types

Ralph J. Abi-Habib, Ravibhushan Singh, Shihui Liu, Thomas H. Bugge, Stephen H. Leppla, Arthur E. Frankel

Research output: Contribution to journalArticle

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Abstract

Urokinase plasminogen activator (uPA) is a tumor-specific protease highly expressed in several types of solid tumors and rarely present on normal cells tinder physiologic conditions. Due to its high expression on metastatic tumors, several different strategies have been used to target the urokinase system. These have mostly led to tumor growth inhibition rather than tumor regression. A different approach was adopted by replacing the furin activation site on a recombinant anthrax toxin with a urokinase activation site. The resulting toxin, PrAgU2/ FP59, was highly potent against tumors both in vitro and in vivo. In this study, we show that PrAgU2/FP59 is toxic to a wide range of tumor cell lines, including non-small cell lung cancer, pancreatic cancer, and basal-like breast cancer cell lines. Of the few cell lines found to be resistant to PrAgU2/FP59, most became sensitive upon addition of exogenous pro-uPA. PrAgU2/FP59 was much less toxic to normal human cells. The potency of rAgU2/FP59 was dependent on anthrax toxin receptor, PA receptor, and uPA levels but not on total plasminogen activator inhibitor-1 levels. In this study, we show that PrAgU2/FP59 is a wide-range, highly potent, and highly selective toxin that is capable of specifically targeting uPA-expressing tumor cells, independently of the tissue of origin of these cells. Furthermore, we identify three molecular markers, anthrax toxin receptor, uPA, and uPA receptor, which can be used as predictors of tumor cell sensitivity to PrAgU2/FP59.

Original languageEnglish (US)
Pages (from-to)2556-2562
Number of pages7
JournalMolecular Cancer Therapeutics
Volume5
Issue number10
DOIs
StatePublished - Oct 2006

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Urokinase-Type Plasminogen Activator
Plasminogen Activators
Neoplasms
Urokinase Plasminogen Activator Receptors
saruplase
Poisons
Furin
Cell Line
anthrax toxin
Plasminogen Activator Inhibitor 1
Tumor Cell Line
Pancreatic Neoplasms
Non-Small Cell Lung Carcinoma
Peptide Hydrolases
Breast Neoplasms
Growth

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

A urokinase-activated recombinant anthrax toxin is selectively cytotoxic to many human tumor cell types. / Abi-Habib, Ralph J.; Singh, Ravibhushan; Liu, Shihui; Bugge, Thomas H.; Leppla, Stephen H.; Frankel, Arthur E.

In: Molecular Cancer Therapeutics, Vol. 5, No. 10, 10.2006, p. 2556-2562.

Research output: Contribution to journalArticle

Abi-Habib, Ralph J. ; Singh, Ravibhushan ; Liu, Shihui ; Bugge, Thomas H. ; Leppla, Stephen H. ; Frankel, Arthur E. / A urokinase-activated recombinant anthrax toxin is selectively cytotoxic to many human tumor cell types. In: Molecular Cancer Therapeutics. 2006 ; Vol. 5, No. 10. pp. 2556-2562.
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