In this study we use the N-substituted benzamides declopramide (3-CPA) and N-acetyl declopramide (Na-3-CPA) to investigate the involvement of the transcription factor NF-KB in the induction of apoptosis and surface immunoglobulin K (IgK) expression in the mouse pre-B cell line 70Z/3. We first showed that 3-CPA-induced apoptosis at doses around 500 muM and that the 3-CPA-induced apoptosis could be suppressed by over-expression of the Bcl-2 protein. Na-3-CPA was shown to be non-apoptotic at doses up to 1-2 mM. On the other hand, Na-3-CPA inhibited LPS-induced IgK expression while 3-CPA had no effect. Further analysis showed that while 3-CPA inhibited breakdown of IKBalpha, Na-3-CPA inhibited breakdown of IKBbeta. In addition, we used a 70Z/3 cell line expressing a dominant negative IKBalpha (70Z/3(DeltaNIKBalpha)). The 70Z/3(DeltaNIKBalpha) cell line was shown to be more sensitive to apoptosis and cytotoxicity induced by 3-CPA as well as by LPS, probably due to a defect in NF-KB rescue mechanism. Taken together, our data implicate distinct roles for IKBalpha and IKBbeta in regulating various NF-KB activities. (C) 2002 Elsevier Science (USA). All rights reserved.