摘要
诱导治疗对伴有Mt NPM1的急性髓细胞性白血病具有相对较好的疗效。但是一部分NPMc阳性AML细胞不能被常规疗法所清除。因此,我们通过评价鱼藤素展现出的广泛的生物活性和较低的毒性来评价鱼藤素的治疗效果。我们以前报道了鱼藤素选择性地减少Mt NPM1,也减少NPMc+AML细胞的分化和加强它的细胞凋亡。然而,几乎没有关于鱼藤素诱导分化机制的可用信息。这里,我们研究了鱼藤素在诱导NPMc+AML细胞分化过程中所发挥的作用。鱼藤素在2 μM无毒浓度下,强烈地抑制细胞生长但是减少在OCI-AML3细胞运载的Mt NPM1内的细胞凋亡,反之,其在OCIM2细胞内含Wt NPM1的抗恶性细胞增殖作用极小。相比之下,OCIM2细胞却没有应答,用鱼藤素处理过的OCI-AML3细胞表现出了粒细胞/单核细胞分化的形态特征,增强分化抗原的表达,及氮蓝四唑还原活性。抑制分化与Mt NPM1和SIRT1的向下调节有关,但是却与Wt NPM1无关,Wt NPM1伴随着CEBPβ 和 G-CSFR的表达增加,以及进一步由sh-Mt NPM1和sh-SIRT1所证实。sh-Mt NPM1治疗减少SIRT1表达,但是不改变HDAC1/3水平,意味着SIRT1的下降与鱼藤素诱导,Mt-NPM1相关的分化部分相关。此外,Mt NPM1过表达阻塞了鱼藤素诱导细胞分化。最后,我们揭示了鱼藤素通过泛激素-蛋白酶体途径诱导Mt NPM1表达。综上所述,我们的研究结果表明鱼藤素可能作为治疗NPMc阳性急性髓细胞性白血病的一种潜在候选治疗药物。
关键词: 鱼藤素分化,NPMc+急性髓细胞性白血病
Current Cancer Drug Targets
Title:Nontoxic-dose of Deguelin Induce NPMc+ AML Cell Differentiation by Selectively Targeting Mt NPM1/SIRT1 Instead of HDAC1/3
Volume: 14 Issue: 8
Author(s): You Ping Wang, Sha Yi, Lu Wen, Ben Ping Zhang, Zichu Zhao, Jing Yu Hu, Fei Zhao, Jing He, Jun Fang, Chun Zhang, Guohui Cui and Yan Chen
Affiliation:
关键词: 鱼藤素分化,NPMc+急性髓细胞性白血病
摘要: AML with Mt NPM1 has relatively good responses to induction therapy. However, a proportion of NPMc+ AML cells cannot be cleared by conventional treatments. Therefore, we determined the therapeutic efficacy of deguelin that has demonstrated extensive biological activity with low toxicity. We previously reported that deguelin selectively reduces Mt NPM1, as well as induces differentiation and potentiates apoptosis in NPMc+ AML cells. Nevertheless, little information is available regarding the mechanism of deguelin-induced differentiation. Here, we investigated the role of deguelin in the induction of NPMc+ AML cell differentiation. Deguelin at the nontoxic concentration of 2 μM strongly inhibited cell growth but reduced apoptosis in OCI-AML3 cells carrying Mt NPM1, whereas the antiproliferative effect was minimal in OCIM2 cells harboring Wt NPM1. Compared with OCIM2 cells that showed no response, deguelintreated OCI-AML3 cells exhibited the morphological features of granulocytic/monocytic differentiation, increased expression of differentiation antigens, and a nitroblue tetrazolium reduction activity. Induction of differentiation was associated with downregulation of Mt NPM1 and SIRT1, but not Wt NPM1, which was accompanied by an increase in CEBPβ and G-CSFR expression, and further confirmed by sh-Mt NPM1 and sh-SIRT1. sh-Mt NPM1 treatment reduced SIRT1 expression, but did not change HDAC1/3 levels, suggesting that the decline of SIRT1 was partially accountable for the deguelin-induced, Mt-NPM1-related differentiation. Moreover, Mt NPM1 overexpression blocked deguelin-induced cell differentiation. Lastly, we showed that deguelin reduced the expression of Mt NPM1 via the ubiquitin-proteasome pathway. Taken together, our results suggest that deguelin may be a therapeutic candidate for NPMc+ AML.
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You Ping Wang, Sha Yi, Lu Wen, Ben Ping Zhang, Zichu Zhao, Jing Yu Hu, Fei Zhao, Jing He, Jun Fang , Chun Zhang, Guohui Cui and Chen Yan, Nontoxic-dose of Deguelin Induce NPMc+ AML Cell Differentiation by Selectively Targeting Mt NPM1/SIRT1 Instead of HDAC1/3, Current Cancer Drug Targets 2014; 14 (8) . https://dx.doi.org/10.2174/1568009614666141028123835
DOI https://dx.doi.org/10.2174/1568009614666141028123835 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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