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Synergistic effect of bortezomib and valproic acid treatment on the proliferation and apoptosis of acute myeloid leukemia and myelodysplastic syndrome cells

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Abstract

The synergistic effect of proteasome inhibitor bortezomib and valproic acid (VPA), a histone deacetylase inhibitor, were investigated in this study. Co-treatment with VPA and bortezomib on acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cell lines resulted in marked inhibition of proliferation and induction of apoptosis, including a striking increase in mitochondrial injury, caspase cascade activation, and altered expression of Bcl-2 family proteins. Moreover, combination treatment inhibited cyto-protective signaling pathways, including inactivation of nuclear factor κB (NF-κB), the extracellular signal-related kinase (ERK) and Akt pathways, and activated stress-related signaling pathway, including the c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38) pathways. In addition, this regimen significantly caused G2/M phase arrest, while downregulating the expression of phospho-CDC2 and CyclinD1 as well as increasing p21cip1. Furthermore, combination treatment efficiently induced apoptosis in primary AML/MDS cells, with little effect on normal cells. In summary, these findings indicate that combination treatment with VPA and bortezomib may be a potent therapy for AML/MDS malignancies.

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Authors and Affiliations

  1. Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai, 200025, China

    Ai-Hua Wang, Lin Wei, Li Chen, Shu-Qing Zhao, Wei-Li Wu, Zhi-Xiang Shen & Jun-Min Li

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  1. Ai-Hua Wang
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  2. Lin Wei
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Correspondence to Jun-Min Li.

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Wang, AH., Wei, L., Chen, L. et al. Synergistic effect of bortezomib and valproic acid treatment on the proliferation and apoptosis of acute myeloid leukemia and myelodysplastic syndrome cells. Ann Hematol 90, 917–931 (2011). https://doi.org/10.1007/s00277-011-1175-6

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  • DOI: https://doi.org/10.1007/s00277-011-1175-6

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