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

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, Gary D. Glick

Research output: Contribution to journalArticle

57 Scopus citations

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 (O2-) in transformed Ramos B cells. This O2- response originated from mitochondria prior to mitochondrial transmembrane gradient collapse and opening of the permeability transition pore. Bz-423-induced O2- 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 O2- or scavenge free radicals attenuated the death cascade, which demonstrated that cell killing by Bz-423 depends on O2-. 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)F1 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.

Original languageEnglish
Pages (from-to)1123-1132
Number of pages10
JournalJournal of Clinical Investigation
Volume110
Issue number8
DOIs
StatePublished - Oct 2002
Externally publishedYes

Fingerprint Dive into the research topics of 'Benzodiazepine-induced superoxide signals B cell apoptosis: Mechanistic insight and potential therapeutic utility'. Together they form a unique fingerprint.

  • Cite this

    Blatt, N. B., Bednarski, J. J., Warner, R. E., Leonetti, F., Johnson, K. M., Boitano, A., Yung, R., Richardson, B. C., Johnson, K. J., Ellman, J. A., Opipari, A. W., & Glick, G. D. (2002). Benzodiazepine-induced superoxide signals B cell apoptosis: Mechanistic insight and potential therapeutic utility. Journal of Clinical Investigation, 110(8), 1123-1132. https://doi.org/10.1172/JCI0216029