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Lymphomas

Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas

Leukemia volume 18, pages 1699–1704 (2004)Cite this article

Abstract

Primary effusion lymphomas (PELs) are a rare type of non-Hodgkin's lymphoma that are resistant to cytotoxic chemotherapy. PELs manifest constitutive activation of nuclear factor kappa B (NF-κB), and inhibition of NF-κB induces apoptosis of PELs and sensitizes to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced death. Bortezomib (PS-341), a peptidyl boronic acid inhibitor of the proteasome, is a potent agent against a wide range of hematologic malignancies and has been shown to inhibit NF-κB. Thus, we examined the cytotoxic effects of bortezomib alone and in combination with various drugs. Bortezomib potently inhibited NF-κB in PEL cells in a dose-dependent manner. In addition, bortezomib inhibited growth and induced apoptosis of PEL cell lines (IC50 values of 3.4–5.0 nM). Results of drug interactions between bortezomib and chemotherapy (doxorubicin and Taxol) were schedule-dependent: synergistic interactions were generally observed when PEL cells were pretreated with bortezomib prior to chemotherapy, whereas additive or even antagonistic interactions occurred with chemotherapy pretreatment or simultaneous treatment with bortezomib and chemotherapy. Most schedules of bortezomib and dexamethasone were synergistic, although pretreatment with dexamethasone resulted in additive interactions. Effects of combinations of bortezomib and TRAIL were generally additive. Thus, bortezomib represents a promising potential therapy for the treatment of PEL.

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Acknowledgements

Supported by grants from the National Institutes of Health (5R01CA80004) and the American Cancer Society (RPG-00-305-01-MBC) to MBR. In addition to supplying bortezomib, Millennium Pharmaceuticals, Incorporated, also provided financial support for this study.

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Authors and Affiliations

  1. VA Greater Los Angeles Healthcare System, Los Angeles, 90073, CA, USA

    J An, Y Sun, M Fisher & M B Rettig

  2. Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, 90095, CA, USA

    M B Rettig

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  1. J An
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  4. M B Rettig
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Correspondence to M B Rettig.

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An, J., Sun, Y., Fisher, M. et al. Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas. Leukemia 18, 1699–1704 (2004). https://doi.org/10.1038/sj.leu.2403460

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