N-substituted benzamides inhibit NF kappa B activation and induce apoptosis by separate mechanisms

Benzamides have been in clinical use for many years in treatment against va rious disorders. A recent application is that as a sensitizer for radio- or chemotherapies, We have here analysed the mechanism of action of N-substit uted benzamides using an in vitro system. We found that while procainamide was biologically inert in our system, the addition of a chloride in the 3' position of the benzamide ring created a compound (declopramide) that induc ed rapid apoptosis. Furthermore, declopramide also inhibited NF kappa B act ivation by inhibition of I kappa B beta breakdown. An acetylated Variant of declopramide, N-acetyl declopramide, showed no effect with regard to rapid apoptosis induction but was a potent inhibitor of NF kappa B activation. I n fact, the addition of an acetyl group to procainamide in the 4' position was sufficient to convert this biologically inactive substance to a potent inhibitor of NF kappa B activation. These findings suggest two potential me chanisms, induction of early apoptosis and inhibition of NF kappa B mediate d salvage from apoptosis, for the biological effect of N-substituted benzam ides as radio- and chemo-sensitizers. In addition it suggests that N-substi tuted benzamides are potential candidates for the development of anti-infla mmatory compounds using NF kappa B as a drug target. (C) 1999 Cancer Resear ch Campaign.