title: Cisplatin inhibition of anthrax lethal toxin.
abstract: 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.
authors.affiliation: Bacterial Toxins and Therapeutics Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Mahtab
authors.initials: M
authors.lastname: Moayeri
authors.forename: Jason F
authors.initials: JF
authors.lastname: Wiggins
authors.forename: Robin E
authors.initials: RE
authors.lastname: Lindeman
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
mesh_terms: D000818:Animals; D000881:Anthrax / Q000188:drug therapy; D000942:Antigens, Bacterial / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005098:Exotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
chemical_list: D000942:Antigens, Bacterial; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D005098:Exotoxins; C030325:anthrax toxin; D002945:Cisplatin