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The Proteasome Inhibitor Bortezomib Acts Independently of p53 and Induces Cell Death via Apoptosis and Mitotic Catastrophe in B-Cell Lymphoma Cell Lines

¹ Cancer Research UK Medical Oncology Unit, St. Bartholomew's Hospital; ² Department of Haematology, Bart's and The London School of Medicine and Dentistry, London, United Kingdom; and ³ Millennium Pharmaceuticals, Cambridge, Massachusetts

Requests for reprints: Simon P. Joel, Barry Reed Oncology Laboratory, 38 Little Britain, West Smithfield, London EC1A 7BE, United Kingdom. Phone: 44-207-601-8924; Fax: 44-207-600-4265; E-mail: s.p.joel{at}qmul.ac.uk.

Bortezomib is a proteasome inhibitor with proven efficacy in multiple myeloma and non–Hodgkin's lymphoma. This study reports the effects of bortezomib in B-cell lymphoma cell lines with differing sensitivity to bortezomib to investigate factors that influence sensitivity. Bortezomib induced a time- and concentration-dependent reduction in cell viability in five lymphoma cell lines, with EC₅₀ values ranging from 6 nmol/L (DHL-7 cells) to 25 nmol/L (DHL-4 cells) after 72 h. Bortezomib cytotoxicity was independent of p53 function, as all cell lines exhibited mutations by sequence analysis. The difference in sensitivity was not explained by proteasome or nuclear factor-B (NF-B) inhibition as these were similar in the most and least sensitive cells. NF-B inhibition was less marked than that of a specific NF-B inhibitor, Bay 11-7082. Cell cycle analysis showed a marked G₂-arrested population in the least sensitive DHL-4 line only, an effect that was not present with Bay 11-7082 treatment. Conversely, in DHL-7 cells, bortezomib treatment resulted in cells moving into an aberrant mitosis, indicative of mitotic catastrophe that may contribute to increased sensitivity to bortezomib. These studies show that although bortezomib treatment had similar effects on apoptotic and NF-B signaling pathways in these cell lines, different cell cycle effects were observed and induction of a further mechanism of cell death, mitotic catastrophe, was observed in the more sensitive cell line, which may provide some pointers to the difference in sensitivity between cell lines. An improved understanding of how DHL-7 cells abrogate the G₂-M cell cycle checkpoint may help identify targets to increase the efficacy of bortezomib. [Cancer Res 2007;67(6):2783–90]

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