Cisplatin inhibition of anthrax lethal toxin

Antimicrob Agents Chemother. 2006 Aug;50(8):2658-65. doi: 10.1128/AAC.01412-05.


Bacillus anthracis lethal toxin (LT) produces symptoms of anthrax in mice and induces rapid lysis of macrophages derived from certain inbred strains. LT is comprised of a receptor binding component, protective antigen (PA), which delivers the enzymatic component, lethal factor (LF), into cells. We found that mouse macrophages were protected from toxin by the antitumor drug cis-diammineplatinum (II) dichloride (cisplatin). Cisplatin was shown to inhibit LT-mediated cleavage of cellular mitogen-activated protein kinases (MEKs) without inhibiting LF's in vitro proteolytic activity. Cisplatin-treated PA lost 100% of its ability to function in toxicity assays when paired with untreated LF, despite maintaining the ability to bind to cells. Cisplatin-treated PA was unable to form heptameric oligomers required for LF binding and translocation. The drug was shown to modify PA in a reversible noncovalent manner. Not surprisingly, cisplatin also blocked the actions of anthrax edema toxin and of LF-Pseudomonas aeruginosa exotoxin A fusion peptide (FP59), both of which require PA for translocation. Treatment of BALB/cJ mice or Fischer F344 rats with cisplatin at biologically relevant concentrations completely protected the animals from a coadministered lethal dose of LT. However, treatment with cisplatin 2 hours before or after animals received a lethal bolus of toxin did not protect them.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Anthrax / drug therapy
  • Antigens, Bacterial / toxicity*
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Bacterial Toxins / antagonists & inhibitors*
  • Bacterial Toxins / toxicity*
  • Cell Line
  • Cell Survival / drug effects
  • Cisplatin / administration & dosage
  • Cisplatin / pharmacology*
  • Dose-Response Relationship, Drug
  • Exotoxins / antagonists & inhibitors*
  • Exotoxins / toxicity*
  • Injections, Intraperitoneal
  • Injections, Intravenous
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Rats
  • Rats, Inbred F344
  • Time Factors


  • Antigens, Bacterial
  • Antineoplastic Agents
  • Bacterial Toxins
  • Exotoxins
  • anthrax toxin
  • Cisplatin