Serine and matrix metalloproteinase inhibition for malignant astrocytoma therapy.

丝氨酸和基质金属蛋白酶抑制用于恶性星形细胞瘤治疗。

• 批准号: 11671406
• 负责人: YAMAMOTO Masaaki
• 金额: $ 2.18万
• 依托单位: Fukuoka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671406/
• 关键词: malignant astrocytoma; uPA; gelatinase; IRP; NF-kB; invasion; TNF-alpha; RAP; 蛋白分解酵素; NF-kB

In this study, we investigated that the role of NF-kB for regulation of the expression of urokinase-type plasminogen activator (uPA) and signal transduction in tumor necrosis factor-α (TNF-α)-induced cytotoxicity. We found that NF-kB (p50 and p65 subunits) is activated in human astrocytomas in vivo and in vitro, which contributed the overexpression of uPA.Activation of nuclear factor-κB (NF-κB) protects against TNF-α-induced apoptosis in human glioblastoma cells in vitro. The results of zymography and in vitro invasion assay showed that NF-kB inhibitors (steroid, aspirin and pentoxyfiline) suppressed the expression of uPA and invasiveness of human glioblastoma cells in vitro. This effect was accelerated by BB-94, gelatinase inhibitor. Combined with NF-kB inhibitors and recombinant human TNF-alpha, the invasive potential of human glioblastoma cells decreased and induced apoptosis in glioblastoma cells. Our results suggest that the constitutive activation of NF-κB subunits in malignant astrocytoma is realistic traget for malignant astrocytomas therapy modifying the serine and matrix metalloproteinase activities.

本研究探讨了NF-kB在肿瘤坏死因子-α（TNF-α）诱导的细胞毒作用中对尿激酶型纤溶酶原激活物（uPA）表达的调控及信号转导的作用。我们在体内和体外研究中发现，人星形细胞瘤中NF-κ B（p50和p65亚基）均被激活，导致uPA的过度表达，而NF-κ B的激活对TNF-α诱导的人胶质母细胞瘤细胞凋亡具有保护作用。酶谱分析和体外侵袭实验结果表明，NF-kB抑制剂（类固醇、阿司匹林和pentoxyfiline）可抑制uPA的表达和人胶质母细胞瘤细胞的体外侵袭能力。明胶酶抑制剂BB-94可加速这种作用。与NF-kB抑制剂和重组人TNF-α组合，人胶质母细胞瘤细胞的侵袭潜力降低，并诱导胶质母细胞瘤细胞凋亡。我们的研究结果表明，恶性星形细胞瘤中NF-κB亚基的组成性激活是恶性星形细胞瘤治疗的现实目标，改变丝氨酸和基质金属蛋白酶活性。

项目成果

Shuji Hagashi,Masauki Yamamoto: "Expression of nuclear factor-κB, tumor necrosis, factor receptor type 1 and c-Myc in human astrocytoma."Neurologia medico-chirurgica (Tokyo). (発表予定).

Shuji Hagashi、Masauki Yamamoto：“核因子-κB、肿瘤坏死、因子受体 1 型和 c-Myc 在人星形细胞瘤中的表达。Neurologia medico-chirurgica（东京）。”

Masaaki Yamamoto: "Correlation of the expression of nuclar tictor-KB,tumor necrosis foction reception types 1(TNFR1) and C-Mye with the treatment of recomlinent TNF-d"Anticancer Besearch. (発表予定).

Masaaki Yamamoto：“核因子-KB、肿瘤坏死因子接收类型 1 (TNFR1) 和 C-Mye 的表达与复发 TNF-d 治疗的相关性”抗癌研究（待提交）。

Masaaki Yamainoto: "Correlation of the expression of nuclear factor-κB, tumor necrosis factor receptor type I (TNFRI) and c-Myc with the clinical course in the treatment of malignant astrocytomas with recombinant mutant human tumor necrosis factor-alpha (

Masaaki Yamainoto：“核因子-κB、I 型肿瘤坏死因子受体 (TNFRI) 和 c-Myc 的表达与重组突变型人肿瘤坏死因子-α 治疗恶性星形细胞瘤临床过程的相关性（

Shuji Hayashi Masaaki Yamamoto: "Expression of nuclear factor-κB, tumor mecrosis factor receptor type 1, and c-Myc in human astrocytomas"Neurologia medico-chirungica (Tokyo). (発表予定).

Shuji Hayashi Masaaki Yamamoto：“核因子-κB、肿瘤坏死因子受体 1 型和 c-Myc 在人星形细胞瘤中的表达”Neurologia medico-chirungica（东京）（即将发表）。

Masaaki Yamamoto: "Correlation of the expression of nuclear factor -κB, tumor necrosis factor receptor type 1 and c-Myc with clinical course in the treatment of malignant astrocytoma"Anticancer Research. 20. 611-618 (2000)

Masaaki Yamamoto：“核因子-κB、肿瘤坏死因子受体1型和c-Myc的表达与恶性星形细胞瘤治疗的临床过程的相关性”Anticancer Research 20. 611-618 (2000)。