THE PROTEASOME INHIBITOR LACTACYSTIN INDUCES APOPTOSIS AND SENSITIZESCHEMORESISTANT AND RADIORESISTANT HUMAN CHRONIC LYMPHOCYTIC-LEUKEMIA LYMPHOCYTES TO TNF-ALPHA-INITIATED APOPTOSIS

Apoptosis can be triggered by cytotoxic agents and radiation currently used in cancer treatment. However, the apoptotic response appears to vary between cell types (normal or transformed) and between types of m alignancy. Thus, irradiation induces apoptosis in normal human lymphoc ytes but not in lymphocytes derived from a subset of chronic lymphocyt ic leukaemia (CLL). Moreover, in this subset, spontaneous apoptosis is inhibited by irradiation. Why irradiation does not allow the initiati on of the apoptotic, death pathway could be explained, at least in par t, and in agreement with recent findings on experimental models, by th e activation of the transcriptional factor NF-kappa B, which is able t o inhibit apoptotic cell response. Low doses (at which no effect is ob served with normal human lymphocytes) of the highly specific proteasom e inhibitor lactacystin are sufficient to trigger apoptosis in these m alignant cells. Proteasome inhibition by lactacystin prevents the nucl ear translocation of both p50 and p65 NF-kappa B subunits and sensitiz es these cells to apoptosis by tumour necrosis factor (TNF)-alpha trea tment. As this subset of CLL is totally resistant to any treatment, pr oteasome inhibition by lactacystin provides a new therapeutic approach to be explored, considering the sensitivity of malignant CLL-derived lymphocytes to be quite different from that of normal human lymphocyte s.