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Apoptosis

The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis

Abstract

Interactions between inhibitors of the proteasome and histone deacetylases have been examined in human T-leukemia/lymphoma cells both in vitro and in vivo. Co-exposure of cells to bortezomib and suberoylanilide hydroxamic acid (SAHA) synergistically induces T-leukemia/lymphoma cells to undergo apoptosis, consistent with a significant increase in mitochondrial injury and caspase activation. These events are accompanied by inhibition of cyto-protective signaling pathways, including the nuclear factor (NF)-κB, Raf-1/mitogen-induced extracellular kinase (MEK)/extracellular signal-related kinase (ERK) and AKT pathways, and activation of stress-related cascades, including the stress-activated kinases c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK). Moreover, bortezomib in conjunction with SAHA efficiently induces apoptosis of primary T-leukemia/lymphoma cells and inhibits tumor growth in a murine xenograft model established with subcutaneous injection of Jurkat cells. Taken together, these findings confirm the synergistic anti-tumor effect of the proteasome and histone deacetylase inhibitors, and provide an insight into the future clinical applications of bortezomib–SAHA combining regimen in treating T-cell malignancies.

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Acknowledgements

We thank Professor Arthur Zelent for his critical review of the paper. This work was supported, in part, by the Chinese National Key Program for Basic Research (973:2004CB518600), the Chinese National High Tech Program (863:2006AA02A301 and 863:2006AA02A405), the National Natural Science Foundation of China (30750335), the Shanghai Commission of Science and Technology (08410708800), the Shanghai Rising Star Program (05QMX1429), the Program for New Century Excellent Talents in University, the Scientific Research Foundation for the Returned Overseas Chinese Scholars, the Fok Ying Tung Education Foundation (111035), the Programme de Recherches Avancées, the Samuel Waxman Cancer Research Foundation Laboratory and by the Co-PI Program of Shanghai Rui Jin Hospital/Shanghai Jiao Tong University School of Medicine.

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Correspondence to W-L Zhao.

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Zhang, QL., Wang, L., Zhang, YW. et al. The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis. Leukemia 23, 1507–1514 (2009). https://doi.org/10.1038/leu.2009.41

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