Annals of Hematology

, Volume 90, Issue 8, pp 917–931

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

Authors

  • Ai-Hua Wang
    • Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Ruijin HospitalShanghai Jiao-Tong University School of Medicine
  • Lin Wei
    • Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Ruijin HospitalShanghai Jiao-Tong University School of Medicine
  • Li Chen
    • Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Ruijin HospitalShanghai Jiao-Tong University School of Medicine
  • Shu-Qing Zhao
    • Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Ruijin HospitalShanghai Jiao-Tong University School of Medicine
  • Wei-Li Wu
    • Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Ruijin HospitalShanghai Jiao-Tong University School of Medicine
  • Zhi-Xiang Shen
    • Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Ruijin HospitalShanghai Jiao-Tong University School of Medicine
    • Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Ruijin HospitalShanghai Jiao-Tong University School of Medicine
Original Article

DOI: 10.1007/s00277-011-1175-6

Cite this article as:
Wang, A., Wei, L., Chen, L. et al. Ann Hematol (2011) 90: 917. doi:10.1007/s00277-011-1175-6

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.

Keywords

BortezomibValproic acidAcute myeloid leukemiaMyelodysplastic syndrome

Copyright information

© Springer-Verlag 2011