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

doi:10.1016/j.exphem.2007.06.009

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Volume 35, Issue 12 , Pages 1801-1811, December 2007

Combined effects of histone deacetylase inhibitor and rituximab on non-Hodgkin's B-lymphoma cells apoptosis

Wei-Li Zhao
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Drs. Zhao, Wang, Liu, and Yan contributed equally to this work.
Lan Wang
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Health Science, Shanghai Institutes for Biological Sciences and Graduate School, Chinese Academy of Sciences and School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Drs. Zhao, Wang, Liu, and Yan contributed equally to this work.
Yuan-Hua Liu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Drs. Zhao, Wang, Liu, and Yan contributed equally to this work.
Jin-Song Yan
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Drs. Zhao, Wang, Liu, and Yan contributed equally to this work.
Christophe Leboeuf
- Unité INSERM U728/Université Paris VII, Institut d'Hématologie, Hôpital Saint Louis, Paris, France
Yan-Yan Liu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Wei-Li Wu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Anne Janin
- Unité INSERM U728/Université Paris VII, Institut d'Hématologie, Hôpital Saint Louis, Paris, France
Zhu Chen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Health Science, Shanghai Institutes for Biological Sciences and Graduate School, Chinese Academy of Sciences and School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Sai-Juan Chen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Health Science, Shanghai Institutes for Biological Sciences and Graduate School, Chinese Academy of Sciences and School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Offprint requests to: Sai-Juan Chen, M.D., Ph.D., State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai 200025, China

Received 17 January 2007; received in revised form 18 May 2007; accepted 6 June 2007. published online 03 August 2007.

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.