Abstract
Adult T-cell leukemia (ATL) is a fatal neoplasm derived from CD4-positive T-lymphocytes, and regardless of intensive chemotherapy, its mean survival time is less than 1 year. Nuclear factor-κB (NF-κB) activation was reported in HTLV-I associated cells, and has been implicated in oncogenesis and resistance to anticancer agents and apoptosis. We studied the effect of a proteasome inhibitor, bortezomib (formerly known as PS-341), on ATL cells in vitro and in vivo. Bortezomib could inhibit the degradation of IκBα in ATL cells, resulting in suppression of NF-κB and induction of cell death in ATL cells in vitro. Susceptibilities to bortezomib were well correlated with NF-κB activation, suggesting that suppression of the NF-κB pathway was implicated in the cell death induced by bortezomib. Although the majority of the cell death was apoptosis, necrotic cell death was observed in the presence of a caspase inhibitor, z-VAD-fmk. When bortezomib was administered into SCID mice bearing tumors, it suppressed tumor growth in vivo, showing that bortezomib was effective against ATL cells in vivo. These studies revealed that bortezomib is highly effective against ATL cells in vitro and in vivo by induction of apoptosis, and its clinical application might improve the prognosis of patients with this fatal disease.
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Acknowledgements
We thank E Kodama and S Adachi for their valuable advice, Y Namba for supplying the anti-Tax antibody (MI73), M Maeda for supplying the ATL cell lines, and Y Maeda and K Akasaka for providing samples from ATL patients. We are grateful to P Miyazato and K Doi for their technical assistance. This study was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan.
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Satou, Y., Nosaka, K., Koya, Y. et al. Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro. Leukemia 18, 1357–1363 (2004). https://doi.org/10.1038/sj.leu.2403400
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DOI: https://doi.org/10.1038/sj.leu.2403400
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