Valproic acid enhances the antileukemic effect of cytarabine by triggering cell apoptosis.
Valproic acid enhances the antileukemic effect of cytarabine by triggering cell apoptosis.
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DOI：
10.3892/ijmm.2016.2552
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发表时间：
2016-06
影响因子：
5.4
通讯作者：
Nan Liu;Chen Wang;Libing Wang;Lei Gao;Hui Cheng;G. Tang;Xiaoxia Hu;Jianmin Wang
中科院分区：
文献类型：
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作者：
Nan Liu;Chen Wang;Libing Wang;Lei Gao;Hui Cheng;G. Tang;Xiaoxia Hu;Jianmin Wang
急性髓性白血病（AML）是一种侵袭性的造血祖细胞克隆性恶性肿瘤，临床预后较差。白血病细胞对当代化疗的耐药性是治疗急性髓性白血病的最大障碍之一。丙戊酸（VPA）与其他抗白血病药物联合使用是一种有效且必要的策略，可用于特异性诱导抗癌基因表达。在本研究中，我们在逆转录病毒介导的mml - af9白血病小鼠模型、3种白血病细胞系（THP-1、K562和HL-60）和7种原发性人类AML样本中证明了VPA和阿糖胞苷（Ara‑C）之间的协同抗白血病活性。通过RT-qPCR，我们发现VPA和Ara‑C联合使用可显著上调Bax的表达，抑制白血病细胞增殖、亚g1期DNA积累和细胞凋亡，流式细胞术分析证实了这一点。值得注意的是，进一步的实验表明，敲低Bax表达可阻止VPA和Ara - C诱导的THP-1细胞凋亡。我们目前的研究结果表明，VPA和Ara - C联合治疗AML具有协同抗白血病作用，因此我们建议使用VPA作为AML的替代治疗方法。
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.