Antitumor effect of dehydroxymethylepoxyquinomicin, a small molecule inhibitor of nuclear factor-κB, on glioblastoma
Antitumor effect of dehydroxymethylepoxyquinomicin, a small molecule inhibitor of nuclear factor-κB, on glioblastoma
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DOI：
10.1093/neuonc/nor168
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发表时间：
2012-01-01
期刊：
影响因子：
15.9
通讯作者：
Kataoka, Hiroaki
中科院分区：
文献类型：
--
作者：
Fukushima, Tsuyoshi;Kawaguchi, Makiko;Kataoka, Hiroaki
胶质母细胞瘤是最恶性的脑肿瘤类型。尽管最近在治疗方式上取得了进展，但胶质母细胞瘤的预后仍然非常差。最近的研究表明，RelA/核因子（NF）-κ B在人类胶质母细胞瘤中始终被激活。在这项研究中，我们寻找一种新的治疗胶质母细胞瘤的方式，通过检查的效果去羟甲基表氧喹诺霉素（DHMEQ），一个独特的小分子NF-κ B抑制剂。另外DHMEQ培养的人胶质母细胞瘤细胞抑制RelA的核转位。它还在6个细胞系中显着降低了人胶质母细胞瘤细胞的生长速率，并且在检查的10个细胞系中的3个细胞系中适度降低了生长速率。然后，我们使用3种敏感细胞系（U87、U251和YKG-1）进行进一步分析。在体外培养中，生长迟缓伴有G2/M期阻滞。DHMEQ处理后，U87和YKG-1细胞凋亡增加，但U251细胞未出现凋亡。然后，我们通过使用裸鼠模型测试DHMEQ在化学预防中的功效。通过在植入细胞后立即开始腹膜内施用DHMEQ，由U87或U251细胞形成的皮下肿瘤的大小减小了约40%。DHMEQ治疗在颅内植入U87或U251细胞的小鼠的存活曲线中实现了统计学上显著的改善。组织学分析显示，DHMEQ处理的U87肿瘤组织中坏死面积增加，塌陷微血管数量增加，RelA的核免疫反应性降低，尿激酶型纤溶酶原激活物的免疫反应性降低。这些结果表明，通过DHMEQ靶向NF κ B可以作为胶质母细胞瘤中有希望的治疗方式。
Glioblastoma is the most malignant type of brain tumor. Despite recent advances in therapeutic modalities, the prognosis of glioblastoma remains very poor. Recent studies have indicated that RelA/nuclear factor (NF)-kappa B is consistently activated in human glioblastoma. In this study, we searched for a new treatment modality for glioblastoma, by examining the effects of dehydroxymethylepoxyquinomicin (DHMEQ), a unique small molecule inhibitor of NF-kappa B. Addition of DHMEQ to cultured human glioblastoma cells inhibited the nuclear translocation of RelA. It also reduced the growth rate of human glioblastoma cells significantly in 6 cell lines and modestly in 3 among 10 cell lines examined. Then, we performed further analyses using 3 sensitive cell lines (U87, U251, and YKG-1). The growth retardation was accompanied by G2/M arrest in vitro. Increased apoptosis was observed in U87 and YKG-1, but not U251 cells after DHMEQ treatment. Then, we tested the efficacy of DHMEQ in chemoprevention through the use of a nude mouse model. Subcutaneous tumors formed by U87 or U251 cells were reduced by similar to 40% in size by intraperitoneal administration of DHMEQ started immediately after implantation of the cells. DHMEQ treatment achieved statistically significant improvements in survival curves of mice intracranially implanted with U87 or U251 cells. Histological analysis revealed increased areas of necrosis, increased numbers of collapsed microvessels, decreased nuclear immunoreactivity of RelA, and decreased immunoreactivity of urokinase-type plasminogen activator in the DHMEQ-treated U87 tumor tissues. These results suggest that the targeting of NFkB by DHMEQ may serve as a promising treatment modality in glioblastoma.