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Apoptosis

Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cδ

Leukemia volume 21, pages 1488–1495 (2007)Cite this article

Abstract

Arsenic trioxide (ATO) and proteasome inhibitor bortezomib have been successfully applied to treat acute promyelocytic leukemia (APL) and multiple myeloma (MM), respectively. Their synergistic effects with other anticancer drugs have been widely studied. Here, we investigated the potential synergy of bortezomib and ATO on Bcr-Abl+ leukemic K562 cells. The results showed that cotreatment of bortezomib at 32 nM, a half concentration for growth arrest, and ATO at 1 μ M, a dose with no significant cytotoxic effect, synergistically induced apoptosis in the cell line, followed by enhanced mitochondrial dysfunction, release of cytochrome c and apoptosis-inducing factor, caspase-3 cleavage and degradation of poly-adenosine diphosphate-ribose polymerase together with the decreased Bcr-Abl protein. These two drugs synergistically induced proteolytic activation of protein kinase Cδ (PKCδ) with enhanced activation of two mitogen-activated protein kinases phospho-c-Jun NH2-terminal kinase and p38. The specific PKCδ inhibitor rottlerin markedly decreased bortezomib plus ATO-induced apoptosis, suggesting that PKCδ plays an important role in bortezomib plus ATO-induced apoptosis. Moreover, apoptosis synergy of bortezomib and ATO could also be seen in some kinds of acute leukemic cell lines and primary cells. Totally, our results indicate that combined regimen of bortezomib and ATO might be a potential therapeutic remedy for the treatment of leukemia.

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Acknowledgements

This work was supported in part by the National Natural Science Foundation (30630034), National 973 Program (NO2002CB512805) of China and Grants from Science and Technology Committee of Shanghai (05JC14032, 05QMX1425). Dr GQ Chen is a Chang Jiang Scholar of Ministry of Education of China and is supported by Shanghai Ling-Jun Talent Program.

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  1. H Yan, Y-C Wang and D Li: These authors equally contributed to this work

Authors and Affiliations

  1. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine (SJU-SM, formerly Shanghai Second Medical University), Shanghai, China

    H Yan, Y-C Wang, D Li, W Liu, Y-L Wu & G-Q Chen

  2. Department of Hematology, Rui-Jin Hospital, SJU-SM

    H Yan & Y Wang

  3. Division of Functional Genomics of Cancer, Institute of Health Science, SJTU-SM/Shanghai Institutes for Biological Sciences, Shanghai, China

    G-Q Chen

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Yan, H., Wang, YC., Li, D. et al. Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cδ. Leukemia 21, 1488–1495 (2007). https://doi.org/10.1038/sj.leu.2404735

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