Histone Deacetylase Inhibitor Promotes Rituximab-Induced Apoptosis in Non-Hodgkin’s B-Lymphoma Cells by NF-kB-Mediated Bcl-2/Bcl-XL Downregulation and c-Myc Degradation.
(2006)
Journal - ASH Annual Meeting Abstracts
Abstract :
Abstract
The anti-CD20 monoclonal antibody rituximab has shown promisingresults in the clinical treatment of patients with B-cell non-Hodgkin’slymphoma (B-NHL). However, its therapeutic effect could stillbe improved. This study examined the anti-tumor activity ofrituximab combined with histone deacetylase inhibitor suberoylanilidehydroxamic acid (SAHA) in CD20-positivie B-NHL cell lines, aswell as in primary B-NHL cells and a murine B-NHL model. Thecombination treatment sensitized B-NHL cells to apoptosis ina synergistic manner, concomitant with Bcl-2/Bcl-XL downregulation,mitochondrial instability, and caspase activation. Particularlyin Daudi cells relatively insensitive to rituximab, these eventswere associated with nuclear factor-kB (NF-kB) inactivation.SAHA presented functional complementation with rituximab, throughdecreasing IKKa/b and IkBa phosphorylation, thus preventingNF-kB nuclear translocation. In addition, SAHA induced IkBacleavage to a stable inhibitory form and caused NF-kB degradationin response to caspase-3 activation. As an independent approach,co-administration of rituximab and SAHA resulted in a cleardecline in levels of ERK cascade members, including extracellular-signal-regulatedkinase (erk) itself, upstream Raf-1, mitogen-activated proteinkinase/ERK Kinase Kinase-1 (mekk1), and mekk2, as well as theirdownstream transcription factor target c-myc. By western blot,c-Myc protein was subsequently downregulated when treated withrituximab or SAHA, and the degradation was most significantin combination group. More importantly, rituximab-SAHA combinationsignificantly promoted primary B-NHL cells apoptosis and improvedthe survival time of a SCID mouse lymphoma model establishedwith intravenous injection of Daudi cells. Terminal deoxytransferase-catalyzedDNA nick-end labeling and ultrastructural study revealed increasedapoptotic lymphoma cells on mice spleen sections of combinationgroup. Taken together, these findings emphasized the value oftargeting apoptosis signaling pathway in lymphoma therapy. Rituximabin conjunction with histone deacetylase inhibitor may representa novel strategy in treating patients with B-NHL.Footnotes* Corresponding authorDisclosure: No relevant conflicts of interest to declare.