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The Proapoptotic Benzodiazepine Bz-423 Affects the Growth and Survival of Malignant B Cells¹

Departments of Chemistry [A. B., G. D. G.] and Obstetrics and Gynecology [A. W. O.] and Graduate Program in Immunology [G. D. G.], University of Michigan, Ann Arbor, Michigan 48109, and Department of Chemistry, University of California-Berkeley, 724 Latimer Hall, Berkeley, California 94720-1460 [J. A. E.]

Bz-423 is a novel proapoptotic 1,4-benzodiazepine that induces cell death via a superoxide signal. Previous work has shown that Bz-423 ameliorates disease in animal models of systemic lupus erythematosus that also have features of lymphoproliferative disease. Here we describe the effects of Bz-423 against a group of malignant B-cell lines derived from Burkitt’s lymphoma. These experiments demonstrate that Bz-423 has cytotoxic activity against all B-cell lines tested, regardless of EBV status or Bcl-2 and Bcl-x_L expression levels. In addition to its cytotoxic properties, we found that Bz-423 is also a potent antiproliferative agent that induces a G₁-phase arrest independent of p53. Mechanistically, both the cytotoxicity and growth arrest are mediated by increased reactive oxygen species levels and appear independent of binding to the peripheral benzodiazepine receptor. This work further defines the biological activities of Bz-423 that are consistent with those of other compounds in clinical development for antineoplastic therapies.

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