The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-α-initiated apoptosis

Abstract

Summary 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 malignancy. Thus, irradiation induces apoptosis in normal human lymphocytes but not in lymphocytes derived from a subset of chronic lymphocytic leukaemia (CLL). Moreover, in this subset, spontaneous apoptosis is inhibited by irradiation. Why irradiation does not allow the initiation of the apoptotic death pathway could be explained, at least in part, and in agreement with recent findings on experimental models, by the activation of the transcriptional factor NF-KB, which is able to inhibit apoptotic cell response. Low doses (at which no effect is observed with normal human lymphocytes) of the highly specific proteasome inhibitor lactacystin are sufficient to trigger apoptosis in these malignant cells. Proteasome inhibition by lactacystin prevents the nuclear translocation of both p50 and p65 NF-KB subunits and sensitizes these cells to apoptosis by tumour necrosis factor (TNF)-a treatment. As this subset of CLL is totally resistant to any treatment, proteasome 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 lymphocytes.

Protease inhibitors restore radiation‐induced apoptosis to Bcl‐2‐expressing lymphoma cells

“…Results of some studies have implied that NF-B activity must be reversed for proteasome inhibitors to induce apoptosis [6,7,14], but we were unable to demonstrate such a requirement. Although the p50-p50 NF-B dimer form described here may have roles that are distinct from that of classic NF-B, both the p50-p and classic p50-p65 activation pathways rely on the proteasome for processing p105 and I B, respectively [27].…”

“…The potential role of NF-B in such contexts is somewhat unclear. Although in some cases the inhibition of NF-B by proteasome inhibitors was accompanied by sensitization to cell death initiated by TNF-␣, chemotherapeutic agents, or ionizing radiation [6,7,14], other studies did not demonstrate a requirement for loss of NF-B activity [9,13,15]. Taken together, these findings suggest that apoptosis facilitated by proteasome inhibitors may depend on NF-B inhibition only in specific cell types or the methods used to stimulate the death process.…”

Analysis of changes in the proteome of HL-60 promyeloid leukemia cells induced by the proteasome inhibitor PSI

“…Drexler, hannes.drexler@mpi-muenster.mpg.de. 3] and to sensitize tumor cells to radiotherapy [4] as well as to the cytotoxic action of various conventional chemotherapeutic compounds [5][6][7][8][9][10][11]. Following observations in preclinical tumor models, which revealed potent anti-neoplastic and anti-angiogenic properties of proteasome inhibitors also in vivo [5,[12][13][14], bortezomib (PS-341, Velcade®) has recently been approved as the first novel in class proteasome inhibitor for its use in patients suffering from refractory and relapsed multiple myeloma [15].…”

Crucial Role of the Amino-Terminal Tyrosine Residue 42 and the Carboxyl-Terminal PEST Domain of IκBα in NF-κB Activation by an Oxidative Stress

“…Because I B␣ degradation was observed following treatment with H 2 O 2 even when serines 32 and 36 were substituted for alanines, we were interested to know whether this treatment promoted I B␣ phosphorylation at other sites. We examined I B␣ phosphorylation after treatment with H 2 O 2 in the presence of lactacystin, a proteasome inhibitor (28), and several phosphatase inhibitors to abolish phosphorylated I B␣ degradation. Cell extracts were prepared at time points preceding the appearance of nuclear NF-B.…”