Crucial role of heme oxygenase-1 in the sensitivity of acute myeloid leukemia cell line Kasumi-1 to ursolic acid
Crucial role of heme oxygenase-1 in the sensitivity of acute myeloid leukemia cell line Kasumi-1 to ursolic acid
复制标题
血红素加氧酶-1在急性髓系白血病细胞系Kasumi-1对熊果酸敏感性中的关键作用
DOI：
10.1097/cad.0000000000000068
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发表时间：
2014-04-01
影响因子：
2.3
通讯作者：
Zhou, Shengshu
中科院分区：
文献类型：
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作者：
Ma, Dan;Fang, Qin;Zhou, Shengshu
熊果酸（UA）是一种抗白血病的中药，如果来源于食物，则可以安全食用。我们发现UA处理的急性髓性白血病（AML）M2亚型（AML-M2）细胞株Kasumi-1的凋亡率高于其他白血病细胞株，但低于阿拉伯呋喃糖胞苷（Ara-C）处理的细胞凋亡率，提示UA是治疗AML-M2的重要化疗药物。血红素氧合酶-1（HO-1）是一种发挥细胞保护、细胞增殖和耐药性的关键酶。HO-1在Kasumi-1细胞被上调，被处理与低剂量而不是高剂量UA。锌原卟啉（ZnPP）IX抑制HO-1可使UA致敏Kasumi-1细胞，其凋亡率接近Ara-C诱导的凋亡率（P<0.01）。ZnPP的增敏作用与caspase激活、bcl-2下调和PARP激活有关。用慢病毒介导的siRNA沉默HO-1后，UA诱导的细胞增殖与Ara-C诱导的细胞增殖一样增加。ZnPP与UA联合应用能显著延长M2型AML荷瘤小鼠的生存时间，且肿瘤体积和脾脏体积均较小。结果显示，Kasumi-1细胞对UA最敏感，但由于HO-1的上调，其凋亡作用不如Ara-C。通过靶向抑制HO-1，增强UA的体内外抗白血病作用，可有效治疗AML-M2。
Ursolic acid (UA), which has been used extensively as an antileukemic agent in traditional Chinese medicine, is safely edible if originating from food. We found that the apoptotic rate of acute myeloid leukemia (AML) subtype M2 (AML-M2) cell line Kasumi-1 treated by UA was higher than those of other leukemia cell lines, but was not as high as that treated by arabinofuranosyl cytidine (Ara-C), suggesting that UA is an important chemotherapeutic agent to treat AML-M2. Heme oxygenase-1 (HO-1) is a key enzyme exerting potent cytoprotection, cell proliferation, and drug resistance. HO-1 in Kasumi-1 cells was upregulated by being treated with low-dose rather than high-dose UA. Inhibition of HO-1 by zinc protoporphyrin (ZnPP) IX sensitized Kasumi-1 cells to UA, and the apoptotic rate was close to that induced by Ara-C (P<0.01). The sensitizing effect of ZnPP was associated with caspase activation, bcl-2 downregulation, and PARP activation. After silencing HO-1 by siRNA transfection with lentivirus, the cells’ proliferation induced by UA was increased as it was by Ara-C. Furthermore, combining ZnPP with UA prolonged the survival of mice bearing the AML subtype M2 tumor with smaller volume of tumor and size of spleen. The results showed that the Kasumi-1 cell line was the most sensitive to UA, but the apoptotic effect was inferior to that treated by Ara-C because of HO-1 upregulation. AML-M2 can feasibly be treated by target-inhibiting HO-1 that enhances the antileukemia effects of UA in vitro and in vivo.