Abstract
Relapse after treatment is a common and unresolved problem for patients suffering of the B-cell chronic lymphocytic leukemia (B-CLL). Here we investigated the ability of the isopeptidase inhibitor 2cPE to trigger apoptosis in leukemia cells in comparison with bortezomib, another inhibitor of the ubiquitin-proteasome system (UPS). Both inhibitors trigger apoptosis in CLL B cells and gene expression profiles studies denoted how a substantial part of genes up-regulated by these compounds are elements of adaptive responses, aimed to sustain cell survival. 2cPE treatment elicits the up-regulation of chaperones, proteasomal subunits and elements of the anti-oxidant response. Selective inhibition of these responses augments apoptosis in response to 2cPE treatment. We have also observed that the product of the ataxia telangiectasia mutated gene (ATM) is activated in 2cPE treated cells. Stimulation of ATM signaling is possibly dependent on the alteration of the redox homeostasis. Importantly ATM inhibition, mutations or down-modulation increase cell death in response to 2cPE. Overall this work suggests that 2cPE could offer new opportunities for the treatment of B-CLL.
Highlights
B-cell chronic lymphocytic leukemia (B-CLL) is the most prevalent leukemia in Western countries and it is characterized by accumulation of malignant cells in the blood, lymph nodes, spleen and bone marrow
We investigated the ability of the isopeptidase inhibitor 2cPE to trigger apoptosis in leukemia cells in comparison with bortezomib, another inhibitor of the ubiquitin-proteasome system (UPS)
Both inhibitors trigger apoptosis in CLL B cells and gene expression profiles studies denoted how a substantial part of genes up-regulated by these compounds are elements of adaptive responses, aimed to sustain cell survival. 2cPE treatment elicits the up-regulation of chaperones, proteasomal subunits and elements of the anti-oxidant response
Summary
B-cell chronic lymphocytic leukemia (B-CLL) is the most prevalent leukemia in Western countries and it is characterized by accumulation of malignant cells in the blood, lymph nodes, spleen and bone marrow. B-CLL is a severe disease with heterogeneous clinical course and new therapies have significantly prolonged the overall survival, most patients relapse [1]. Among drugs tested for the ability to trigger apoptosis in B-CLL cells, inhibitors of the ubiquitinproteasome system (UPS) have raised some interest. Bortezomib, the first UPS inhibitor approved for the use in clinic, efficiently triggers apoptosis in in vitro cultured B-CLL cells [6, 7]. Clinical trials evaluating bortezomib in B-CLL patients were unsatisfactory [8]. Evaluating alternative compounds targeting the UPS for the treatment of B-CLL is of primary importance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
