title: Valproic acid enhances the antileukemic effect of cytarabine by triggering cell apoptosis.
abstract: Acute myeloid leukemia (AML) is an aggressive clonal malignancy of hematopoietic progenitor cells with a poor clinical outcome. The resistance of leukemia cells to contemporary chemotherapy is one of the most formidable obstacles to treating AML. Combining valproic acid (VPA) with other anti-leukemic agents has previously been noted as a useful and necessary strategy which can be used to specifically induce anticancer gene expression. In the present study, we demonstrated the synergistic antileukemic activities between VPA and cytarabine (Ara‑C) in a retrovirus-mediated murine model with MLL-AF9 leukemia, three leukemia cell lines (THP-1, K562 and HL-60) and seven primary human AML samples. Using RT-qPCR, we noted that the combination of VPA and Ara‑C significantly upregulated Bax expression and led to the arrest of leukemia cell proliferation, sub-G1 DNA accumulation and cell apoptosis, as demonstrated by flow cytometric analysis. Significantly, further experiments revealed that knockdown of Bax expression prevented VPA and Ara‑C‑induced cell apoptosis in THP-1 cells. The results of our present study demonstrated the synergistic antileukemic effect of combined VPA and Ara‑C treatment in AML, and thus we suggest that VPA be used an alternative treatment for AML.
authors.affiliation: Institute of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Nan
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Traditional Chinese Medicine, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institute of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Libing
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Gao
authors.affiliation: Institute of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Institute of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Gusheng
authors.initials: G
authors.lastname: Tang
authors.affiliation: Institute of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Hu
authors.affiliation: Institute of Hematology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, P.R. China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D061251:Primary Cell Culture; D015398:Signal Transduction; D016019:Survival Analysis; D014635:Valproic Acid / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; C494826:BAX protein, human; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D051028:bcl-2-Associated X Protein; D003561:Cytarabine; D014635:Valproic Acid