Abstract
MS-275 is a histone deacetylase (HDAC) inhibitor that has been reported to mediate its cytotoxic effect through generation of reactive oxygen species (ROS) in proliferating hematopoietic cell lines. We examined efficacy of MS-275 in nonproliferating chronic lymphocytic leukemia (CLL) cells from patients. In these cells, MS-275 demonstrated an in vitro LC50 that was one log lower than for normal mononuclear cells. Following MS-275 treatment, histones H3 and H4 showed increased acetylation and HDAC enzymatic activity was reduced. Caspase-8, -9, and -3 were activated, and caspase substrates PARP and BID were cleaved. Additionally, FLICE-inhibitory protein (FLIP) was downmodulated following MS-275 incubation. MS-275 treatment caused detectable ROS generation after 15 h of incubation, which was blocked by the caspase inhibitor Z-VAD-fmk. Overexpression of Bcl-2 protein protected against MS-275-induced apoptosis. These data demonstrate that MS-275 is a promising therapy for the treatment of CLL, but that in contrast to previous reports, ROS generation does not precede commitment to apoptosis. Similar to many other therapeutic targets, MS-275-mediated apoptosis is reduced by overexpression of Bcl-2, justifying strategies to combine HDAC inhibitors with Bcl-2 antagonists.
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Acknowledgements
We thank Julie Zwiesler and Ronald Mojica for assistance with experiments, Drs Osamu Nakanishi and Schering AG, Berlin, Germany for supplying MS-275; members of Grever and Byrd laboratories for assistance with experiments and helpful comments, and to the many generous CLL patients who donated blood for our research. This work in part is supported by the CLL Research Consortium (P01 CA81534-02) (JCB, MRG, JCR, and SK), The Sidney Kimmel Cancer Research Foundation (JCB), The Leukemia and Lymphoma Society of America (JCB), The D Warren Brown Foundation (JCB), and RPG-00-340-01-CSM from The American Cancer Society (MRP).
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Lucas, D., Davis, M., Parthun, M. et al. The histone deacetylase inhibitor MS-275 induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia cells. Leukemia 18, 1207–1214 (2004). https://doi.org/10.1038/sj.leu.2403388
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DOI: https://doi.org/10.1038/sj.leu.2403388
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