Combined effects of histone deacetylase inhibitor and rituximab on non-Hodgkin's B-lymphoma cells apoptosis.
OBJECTIVE
The anti-CD20 monoclonal antibody rituximab has shown promising results in the clinical treatment of patients with B-cell non-Hodgkin's lymphoma (B-NHL). However, its therapeutic effect could still be improved.


METHODS
This study examined the anti-tumor activity of rituximab combined with histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in CD20-positive B-NHL cell lines, as well as in primary B-NHL cells and a murine B-NHL model.


RESULTS
The combination treatment sensitized B-NHL cells to apoptosis in a synergistic manner, concomitant with mitochondrial instability and Bcl-2/Bcl-XL downregulation. Particularly in Daudi cells relatively resistant to rituximab, these events were associated with nuclear factor-kappaB (NF-kappaB) inactivation and c-Myc degradation. SAHA presented functional complementation with rituximab, through decreasing IKKalpha/beta and IkappaBalpha phosphorylation, thus preventing NF-kappaB nuclear translocation. In addition, SAHA induced IkappaBalpha cleavage to a stable inhibitory form and caused NF-kappaB degradation in response to caspase-3 activation. More importantly, rituximab-SAHA combination significantly promoted primary B-NHL cells apoptosis and improved survival time of a severe combined immunodeficient mouse lymphoma model established with intravenous injection of Daudi cells.


CONCLUSIONS
These findings emphasized the value of targeting apoptosis signaling pathway in lymphoma therapy. Rituximab in conjunction with histone deacetylase inhibitor may represent a novel strategy in treating patients with B-NHL.
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Wei-Li
WL
Zhao
Lan
L
Wang
Yuan-Hua
YH
Liu
Jin-Song
JS
Yan
Christophe
C
Leboeuf
Yan-Yan
YY
Liu
Wei-Li
WL
Wu
Anne
A
Janin
Zhu
Z
Chen
Sai-Juan
SJ
Chen
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D016393:Lymphoma, B-Cell / Q000201:enzymology / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D017931:DNA Primers; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D000069283:Rituximab