An Inhibitor of Arachidonate 5-Lipoxygenase, Nordy, Induces Differentiation and Inhibits Self-Renewal of Glioma Stem-Like Cells
An Inhibitor of Arachidonate 5-Lipoxygenase, Nordy, Induces Differentiation and Inhibits Self-Renewal of Glioma Stem-Like Cells
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Nordy 是一种花生四烯酸 5-脂氧合酶抑制剂，可诱导神经胶质瘤干细胞样细胞的分化并抑制自我更新
DOI：
10.1007/s12015-010-9175-9
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发表时间：
2011-06-01
影响因子：
4.8
通讯作者：
Bian, Xiu-wu
中科院分区：
文献类型：
--
作者：
Wang, Bin;Yu, Shi-cang;Bian, Xiu-wu
癌症生物学的最新进展表明，根除癌症干细胞(CSCs)对于更有效的癌症治疗至关重要。不幸的是，像神经胶质瘤干细胞(GSLCs)这样的癌症干细胞往往对放射或化疗耐药。因此，筛选和开发针对肿瘤干细胞的新的治疗方法已成为癌症研究中的一个重要新兴领域。在本研究中，我们报道了一种人工合成的dl-去甲二氢愈创木酸化合物(dl-NDGA或“NORDY”)，在体外和体内都能抑制GSLCs的自我更新和诱导分化。我们发现，NORDY抑制了一种已知参与白血病干细胞和白血病进展的酶ALOX-5，并在体外抑制了GSLCs的生长。NORDY通过减少CD133(+)群体和取消克隆性来减少GSLC池。NORDY似乎通过上调GFAP和下调茎干相关基因发挥作用，而不是通过诱导GSLCs凋亡来发挥其作用。与烷化剂BCNU相比，NORDY对移植瘤的生长抑制作用更为持久，后者因GSLCs的丰富而导致药物停药的显著复发。同时，短暂暴露于NORDY可降低GSLCs的致瘤性并诱导异种移植物分化。综上所述，我们发现ALOX-5是GSLC中的一个新靶点，其对NORDY的抑制作用可能通过诱导GSLC分化而显示出治疗意义。
Recent progress in cancer biology indicates that eradication of cancer stem cells (CSCs) is essential for more effective cancer therapy. Unfortunately, cancer stem cells such as glioma stem-like cells (GSLCs) are often resistant to either radio- or chemotherapy. Therefore, screening and development for novel therapeutic modalities against CSCs has been an important emerging field in cancer research. In this study, we report that a synthetic dl-nordihydroguaiaretic acid compound (dl-NDGA or "Nordy"), inhibited self-renewal and induced differentiation of GSLCs in vitro and in vivo. We found that Nordy inhibited an enzyme known to be involved in leukemia stem cell and leukemia progression, Alox-5, and attenuated the growth of GSLCs in vitro. Nordy reduced the GSLC pool through a decrease in the CD133(+) population and abrogated clonogenicity. Nordy appeared to exert its effect via astrocytic differentiation by up-regulation of GFAP and down-regulation of stemness related genes, rather than by inducing apoptosis of GSLCs. The growth inhibition of xenografted glioma by Nordy was more long-lasting compared with that of the akylating agent BCNU, which exhibited significant relapse on drug discontinuation resulting from an enrichment of GSLCs. Meanwhile, transient exposure to Nordy reduced tumorigenecity of GSLCs and induced differentiation of the xenografts. Taken together, we have identified Alox-5 as a novel target in GSLCs and its inhibition with Nordy exhibits therapeutic implications through inducing GSLC differentiation.