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Lymphoma

Bortezomib is synergistic with rituximab and cyclophosphamide in inducing apoptosis of mantle cell lymphoma cells in vitro and in vivo

Leukemia volume 22, pages 179–185 (2008)Cite this article

Abstract

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor clinical outcome. Although front therapy induces a high rate of complete remission (CR), relapse is inevitable and new regimens are much needed for relapsed MCL. The proteasome inhibitor bortezomib (BTZ) induces apoptosis and sensitizes MCL cells to chemotherapy in relapsed MCL, but CR rates are low, with a short duration of response and severe toxicity. Here we evaluated whether BTZ is additive or synergistic with cyclophosphamide (CTX) and rituximab (RTX). Increasing doses of BTZ with a fixed dose of RTX and CTX (BRC regimen) resulted in markedly synergistic growth inhibition of MCL cells. BRC significantly enhanced apoptosis in MCL cell lines and primary tumor cells compared with single-agent treatment. Furthermore, western blotting analysis indicated that BRC induces apoptosis earlier via activation and cleavage of caspases-8, -9 and -3, and poly (ADP-ribose) polymerase, than single-agent treatment. The pan-caspase inhibitor completely blocked apoptosis induced by BRC. In vivo studies showed that BRC eradicated subcutaneous tumors in MCL-bearing SCID mice and significantly prolonged the long-term event-free survival in 70% of the mice. Hence, our study demonstrates that cytoreductive chemotherapy with both BTZ and anti-CD20 antibody may offer a better therapeutic modality for relapsed MCL.

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Acknowledgements

This work was supported by institutional start-up funds from The University of Texas M. D. Anderson Cancer Center and funds from the Crutchfield family and the Kimmel family philanthropic foundations. We would like to thank Ms Alison Woo for reviewing and editing this paper.

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Author notes

  1. M Wang, X H Han and L Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cancer Medicine, Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    M Wang, X H Han, L Zhang, J Yang, J F Qian, L W Kwak, J Romaguera & Q Yi

  2. Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

    X H Han & Y K Shi

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  1. M Wang
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  2. X H Han
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Correspondence to Q Yi.

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Wang, M., Han, X., Zhang, L. et al. Bortezomib is synergistic with rituximab and cyclophosphamide in inducing apoptosis of mantle cell lymphoma cells in vitro and in vivo. Leukemia 22, 179–185 (2008). https://doi.org/10.1038/sj.leu.2404959

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