Benzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility.

Abstract

The properties of a proapoptotic 1,4-benzodiazepine, Bz-423, identified through combinatorial chemistry and phenotype screening are described. Bz-423 rapidly generated superoxide (O(2)(-)) in transformed Ramos B cells. This O(2)(-) response originated from mitochondria prior to mitochondrial transmembrane gradient collapse and opening of the permeability transition pore. Bz-423-induced O(2)(-) functioned as an upstream signal that initiated an apoptotic program characterized by cytochrome c release, mitochondrial depolarization, and caspase activation. Pretreatment of cells with agents that either block the formation of Bz-423-induced O(2)(-) or scavenge free radicals attenuated the death cascade, which demonstrated that cell killing by Bz-423 depends on O(2)(-). Parallels between Ramos cells and germinal center B cells prompted experiments to determine whether Bz-423 had therapeutic activity in vivo. This possibility was tested using the (NZB x NZW)F(1) murine model of lupus, in which the pathologically enhanced survival and expansion of germinal center B cells mediate disease. Administration of Bz-423 for 12 weeks specifically controlled germinal center hyperplasia and reduced the histological evidence of glomerulonephritis. Collectively, these studies define a new structure-function relationship for benzodiazepines and point to a new target and mechanism that could be of value for developing improved drugs to manage systemic lupus erythematosus and related disorders.

• Authors: Neal B Blatt, Jeffrey J Bednarski, Roscoe E Warner, Francesco Leonetti, Kathryn M Johnson, Anthony Boitano, Raymond Yung, Bruce C Richardson, Kent J Johnson, Jonathan A Ellman, Anthony W Opipari Jr, Gary D Glick
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 110 Issue 8 Pg. 1123-32 (Oct 2002) ISSN: 0021-9738 [Print] United States
• PMID: 12393848 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Antinuclear
• Reactive Oxygen Species
• Superoxides
• Benzodiazepines
• Bz-423

Topics

• Animals
• Antibodies, Antinuclear (blood)
• Apoptosis (drug effects, physiology)
• B-Lymphocytes (cytology, drug effects, metabolism)
• Benzodiazepines (chemistry, pharmacology)
• Cell Line, Transformed
• Female
• Humans
• In Vitro Techniques
• Lupus Erythematosus, Systemic (drug therapy, immunology, metabolism)
• Mice
• Mice, Inbred NZB
• Models, Biological
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Superoxides (metabolism)