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We evaluated the effects of combined treatment with the proteasome inhibitor bortezomib and the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) on MCL. Bortezomib acts by targeting the proteasome, and \u2013 among other mechanisms \u2013 results in a reduced nuclear factor\u2010kappa B (NF\u2010\u03baB) activity. HDACi promote histone acetylation, and also interfere with NF\u2010\u03baB signaling.<\/jats:p><jats:p><jats:bold>Methods:\u2002<\/jats:bold> Human MCL cell lines (JeKo\u20101, Granta\u2010519 and Hbl\u20102) were exposed to bortezomib and\/or SAHA. Cell viability and apoptosis were quantified by the MTT and annexin\u2010V assay, respectively. Reactive oxygen species (ROS) were analyzed using the fluorophore H<jats:sub>2<\/jats:sub>DCFDA. In addition, activated caspases, proteasome\u2010 and NF\u2010\u03baB activity were quantified.<\/jats:p><jats:p><jats:bold>Results:\u2002<\/jats:bold> Combined incubation with bortezomib and SAHA resulted in synergistic cytotoxic effects, as indicated by combination index values &lt;1 using the median effect method of Chou and Talalay. The combination of both inhibitors led to a strong increase in apoptosis as compared to single agents and was accompanied by enhanced ROS generation, while each agent alone only modestly induced ROS. The free radical scavenger <jats:italic>N<\/jats:italic>\u2010acetyl\u2010<jats:sc>l<\/jats:sc>\u2010cysteine blocked the ROS generation and reduced the apoptosis significantly. In addition, coexposure of bortezomib and SAHA led to increased caspase\u20103, \u20108 and \u20109 activity, marked reduction of proteasome activity and decrease of NF\u2010\u03baB activity.<\/jats:p><jats:p><jats:bold>Conclusions:\u2002<\/jats:bold> This is the first report giving evidence that SAHA and bortezomib synergistically induce apoptosis in MCL cells. These data build the framework for clinical trials using combined proteasome and histone deacetylase inhibition in the treatment of MCL.<\/jats:p>","DOI":"10.1111\/j.1600-0609.2007.00995.x","type":"journal-article","created":{"date-parts":[[2010,7,17]],"date-time":"2010-07-17T21:11:29Z","timestamp":1279401089000},"page":"133-142","source":"Crossref","is-referenced-by-count":90,"title":["Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma"],"prefix":"10.1111","volume":"80","author":[{"given":"Ulrike","family":"Heider","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana 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