THE PROTEASOME INHIBITOR LACTACYSTIN INDUCES APOPTOSIS AND SENSITIZESCHEMORESISTANT AND RADIORESISTANT HUMAN CHRONIC LYMPHOCYTIC-LEUKEMIA LYMPHOCYTES TO TNF-ALPHA-INITIATED APOPTOSIS
J. Delic et al., THE PROTEASOME INHIBITOR LACTACYSTIN INDUCES APOPTOSIS AND SENSITIZESCHEMORESISTANT AND RADIORESISTANT HUMAN CHRONIC LYMPHOCYTIC-LEUKEMIA LYMPHOCYTES TO TNF-ALPHA-INITIATED APOPTOSIS, British Journal of Cancer, 77(7), 1998, pp. 1103-1107
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.