Abstract
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-κB (NF-κB) inactivation and c-Myc degradation. SAHA presented functional complementation with rituximab, through decreasing IKKα/β and IκBα phosphorylation, thus preventing NF-κB nuclear translocation. In addition, SAHA induced IκBα cleavage to a stable inhibitory form and caused NF-κB 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. Conclusion: 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1801-1811 |
| Number of pages | 11 |
| Journal | Experimental Hematology |
| Volume | 35 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2007 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Cell Biology
- Genetics
- Hematology
- Oncology
- Transplantation
Cite this
Combined effects of histone deacetylase inhibitor and rituximab on non-Hodgkin's B-lymphoma cells apoptosis. / Zhao, Wei Li; Wang, Lan; Liu, Yuan Hua; Yan, Jin Song; Leboeuf, Christophe; Liu, Yan Yan; Wu, Wei Li; Janin, Anne; Chen, Zhu; Chen, Sai Juan.
In: Experimental Hematology, Vol. 35, No. 12, 12.2007, p. 1801-1811.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Combined effects of histone deacetylase inhibitor and rituximab on non-Hodgkin's B-lymphoma cells apoptosis
AU - Zhao, Wei Li
AU - Wang, Lan
AU - Liu, Yuan Hua
AU - Yan, Jin Song
AU - Leboeuf, Christophe
AU - Liu, Yan Yan
AU - Wu, Wei Li
AU - Janin, Anne
AU - Chen, Zhu
AU - Chen, Sai Juan
PY - 2007/12
Y1 - 2007/12
N2 - 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-κB (NF-κB) inactivation and c-Myc degradation. SAHA presented functional complementation with rituximab, through decreasing IKKα/β and IκBα phosphorylation, thus preventing NF-κB nuclear translocation. In addition, SAHA induced IκBα cleavage to a stable inhibitory form and caused NF-κB 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. Conclusion: 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.
AB - 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-κB (NF-κB) inactivation and c-Myc degradation. SAHA presented functional complementation with rituximab, through decreasing IKKα/β and IκBα phosphorylation, thus preventing NF-κB nuclear translocation. In addition, SAHA induced IκBα cleavage to a stable inhibitory form and caused NF-κB 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. Conclusion: 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.
UR - http://www.scopus.com/inward/record.url?scp=36248959806&partnerID=8YFLogxK
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U2 - 10.1016/j.exphem.2007.06.009
DO - 10.1016/j.exphem.2007.06.009
M3 - Article
VL - 35
SP - 1801
EP - 1811
JO - Experimental Hematology
JF - Experimental Hematology
SN - 0301-472X
IS - 12
ER -