PROTEASOME INHIBITORS INDUCE APOPTOSIS IN GLUCOCORTICOID-RESISTANT CHRONIC LYMPHOCYTIC LEUKEMIC LYMPHOCYTES

Our previous work showed that the nuclear scaffold (NS) protease is re quired for apoptosis of both thymocytes and chronic lymphocytic leukem ic (CLL) lymphocytes, Because partial sequencing of one of the subunit s of the NS protease revealed homology to the proteasome, we tested th e effects of classical proteasome inhibitors on apoptosis in CLL cells . Here we report that proteasome inhibition caused high levels of DNA fragmentation in all patients analyzed, including those resistant to g lucocorticoids or nucleoside analogs, in vitro. Proteasome inhibitor-i nduced DNA fragmentation was associated with activation of caspase/ICE family cysteine protease(s) and was blocked by the caspase antagonist , zVADfmk, Analysis of the biochemical mechanisms involved showed that proteasome inhibition resulted in mitochondrial dysregulation leading to the release of cytochrome c and a drop in mitochondrial transmembr ane potential (Delta Psi). These changes were associated with inhibiti on of NF kappa B, a proteasome-regulated transcription factor that has been implicated in the suppression of apoptosis in other systems, Tog ether our results suggest that drugs that target the proteasome might be capable of bypassing resistance to conventional chemotherapy in CLL . (C) 1998 by The American Society of Hematology.