{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:09:11Z","timestamp":1790885351707,"version":"4.1.0"},"reference-count":52,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2011,3,6]],"date-time":"2011-03-06T00:00:00Z","timestamp":1299369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2011,4]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Interactions between the histone deacetylase inhibitor belinostat and the proteasome inhibitor bortezomib were investigated in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) cells. Co\u2010administration of sub\u2010micromolar concentrations of belinostat with low nanomolar concentrations of bortezomib sharply increased apoptosis in both AML and ALL cell lines and primary blasts. Synergistic interactions were associated with interruption of both canonical and non\u2010canonical nuclear factor (NF)\u2010\u03baB signalling pathways, e.g. accumulation of the phosphorylated (S32\/S36) form of I\u03baB\u03b1, diminished belinostat\u2010mediated RelA\/p65 hyperacetylation (K310), and reduced processing of p100 into p52. These events were accompanied by down\u2010regulation of NF\u2010\u03baB\u2010dependent pro\u2010survival proteins (e.g. XIAP, Bcl\u2010xL). Moreover, belinostat\/bortezomib co\u2010exposure induced up\u2010regulation of the BH3\u2010only pro\u2010death protein Bim. Significantly, shRNA knock\u2010down of Bim substantially reduced the lethality of belinostat\/bortezomib regimens. Administration of belinostat\u2003\u00b1 bortezomib also induced hyperacetylation (K40) of \u03b1\u2010tubulin, indicating histone deacetylase inhibitor 6 inhibition. Finally, in contrast to the pronounced lethality of belinostat\/bortezomib toward primary leukaemia blasts, equivalent treatment was relatively non\u2010toxic to normal CD34<jats:sup>+<\/jats:sup> cells. Together, these findings indicate that belinostat and bortezomib interact synergistically in both cultured and primary AML and ALL cells, and raise the possibilities that up\u2010regulation of Bim and interference with NF\u2010\u03baB pathways contribute to this phenomenon. They also suggest that combined belinostat\/bortezomib regimens warrant further attention in acute leukaemias.<\/jats:p>","DOI":"10.1111\/j.1365-2141.2011.08591.x","type":"journal-article","created":{"date-parts":[[2011,3,8]],"date-time":"2011-03-08T05:33:21Z","timestamp":1299562401000},"page":"222-235","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Bortezomib interacts synergistically with belinostat in human acute myeloid leukaemia and acute lymphoblastic leukaemia cells in association with perturbations in NF\u2010\u03baB and 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