title: Synergistic effect of bortezomib and valproic acid treatment on the proliferation and apoptosis of acute myeloid leukemia and myelodysplastic syndrome cells.
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 p21(cip1). 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.
authors.affiliation: Department of Hematology, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Ai-Hua
authors.initials: AH
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Wei
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Shu-Qing
authors.initials: SQ
authors.lastname: Zhao
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Wu
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Shen
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Li
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004357:Drug Synergism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology; D011719:Pyrazines; D015398:Signal Transduction / Q000187:drug effects; D014635:Valproic Acid
chemical_list: D001897:Boronic Acids; D018797:Cell Cycle Proteins; D011719:Pyrazines; D014635:Valproic Acid; D000069286:Bortezomib