The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia

@article{Ruiz2006ThePI,
  title={The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia},
  author={Stacey Ruiz and Yelena Krupnik and Michael J. Keating and Joya Chandra and Michael A Palladino and David McConkey},
  journal={Molecular Cancer Therapeutics},
  year={2006},
  volume={5},
  pages={1836 - 1843}
}
Proteasome inhibitors are potent inducers of apoptosis in isolated lymphocytes from patients with chronic lymphocytic leukemia (CLL). However, the reversible proteasome inhibitor bortezomib (PS-341; Velcade) did not display substantial antitumor activity in CLL patients. Here, we compared the effects of bortezomib and a new irreversible proteasome inhibitor (NPI-0052) on 20S chymotryptic proteasome activity and apoptosis in isolated CLL cells in vitro. Although their steady-state (3 hours… 
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References

SHOWING 1-10 OF 41 REFERENCES
Effects of the proteasome inhibitor, bortezomib, on apoptosis in isolated lymphocytes obtained from patients with chronic lymphocytic leukemia.
TLDR
The data confirm that bortezomib, like other proteasome inhibitors, has proapoptotic activity in CLL cells.
A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib.
Treatment of human chronic lymphocytic leukemia cells with the proteasome inhibitor bortezomib promotes apoptosis.
The proteasome inhibitor lactacystin induces apoptosis and sensitizes chemo- and radioresistant human chronic lymphocytic leukaemia lymphocytes to TNF-alpha-initiated apoptosis.
TLDR
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.
In vitro cytotoxic effect of proteasome inhibitor bortezomib in combination with purine nucleoside analogues on chronic lymphocytic leukaemia cells
TLDR
It is suggested that the in vitro cytotoxic effect through proteasome inhibition by bortezomib can be increased substantially with low doses of the purine nucleoside analogues, 2‐CdA and FA, and that this effect on B‐CLL cell is selectively higher than on normal, CD3‐positive lymphocytes.
Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes.
TLDR
The results suggest that drugs that target the proteasome might be capable of bypassing resistance to conventional chemotherapy in CLL, including those resistant to glucocorticoids or nucleoside analogs, in vitro.
Induction of apoptosis by proteasome inhibitors in B-CLL cells is associated with downregulation of CD23 and inactivation of Notch2
TLDR
Downregulation of CD23 and loss of Notch2 activity are early steps in PI-induced apoptosis of B-CLL lymphocytes and may be part of the full apoptotic response.
Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an approximately 700 kDa Apaf-1 containing apoptosome complex.
TLDR
It is suggested that the release of cytochrome c is caspase independent and that caspasing-9 is the initiator casp enzyme in proteasome inhibitor-induced apoptosis of B-CLL cells.
Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an ∼700 kDa Apaf-1 containing apoptosome complex
TLDR
It is suggested that the release of cytochrome c is caspase independent and that caspases-9 is the initiator casp enzyme in proteasome inhibitor-induced apoptosis of B-CLL cells.
Increased sensitivity of CLL‐derived lymphocytes to apoptotic death activation by the proteasome‐specific inhibitor lactacystin
TLDR
An essential role of the ubiquitin system in apoptotic cell death control in CLL lymphocytes is suggested and the inhibition of proteasome‐ubiquitin‐dependent processing could be a discriminatory apoptotic stimulus between normal versus malignant lymphocytes and therefore might potentially be of use in this specific human pathology.
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