Study on differentiation and apoptosis-inducing therapy for head and neck cancer by vesnarinone

维纳里酮诱导头颈癌分化和凋亡的研究

基本信息

批准号：
10307051
负责人：
SATO Mitsunobu
金额：
$ 25.81万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2001
项目状态：
已结题

项目摘要

1. When human oral squamous cell carcinoma cell lines (BHY, HN: p53 wild type (exon4-9)) and human salivary cancer cell lines (HSG, HSG-AZA1, HSG-AZA3: p53 wild type; TYS : p53 codon 281^<Asp→Hls>) were treated with vesnarinone, inhibition of cell growth and induction of G1 arrest occurred in all of the treated cells, where up-regulation of p21^<Waf1>, p27^<Kip1> and TSC-22 genes as well as down-regulation of p53 gene were detected.2. When vesnarinone was administered per os into the nude mice bearing TYS tumors, significant inhibition of the tumor growth as well as cellular differentiation into keratinocyte and acinar cells occurred.3. Vesnarinone was very therapeutically effective for human oral squamous cell carcinoma or for human salivary adenoid cystic carcinoma.4. We isolated and characterized human TSC-22 gene from the TYS cells treated with vesnarinone.(1) Down-regulation of TSC-22 gene in human salivary cancer cells, grown in vitro and in nude mice, caused the marked acceleration of tumor growth and up-regulation of the gene inhibited significantly anchorage-independent growth.(2) Overexpression of TSC-22 protein in TYS cells resulted in the augmented induction of apotosis by anti-cancer drugs (5-FU and CDDP) or radiation.(3) TSC-22 gene was comprised of 3 exons. Transcription initiatin sites were located at 7bp and 29bp downstream from TATA box like sequence. TSC-22 promoter region contained putative binding sites for transcription factor such as NF-kB, MyoD, AP-1, PU, C/EBP, p53, c-Myb, Sp1, NF1 or Smad.5. Sp1 and Sp3 transcription factors bound to the vesnarinone-responsive element (Sp1-1 and Sp1-2 sites) present in p21Waf1 promoter in TYS cells.6. Vesnarinone induced the histone hyperacetylation in TYS cells.

1.当人口腔鳞状细胞癌细胞系（BHY、HN：p53野生型（外显子4-9））和人唾液癌细胞系（HSG、HSG-AZA1、HSG-AZA3：p53野生型；TYS：p53密码子281） ^<Asp→Hls>) 用 vesnarinone 处理，所有处理的细胞均出现细胞生长抑制和 G1 期阻滞诱导，其中上调检测到p21^<Waf1>、p27^<Kip1>和TSC-22基因以及p53基因的下调。2．维纳里酮对TYS瘤裸鼠口服给药，对肿瘤有明显的抑制作用。生长以及细胞分化为角化细胞和腺泡细胞。 3．维纳里酮对人口腔鳞状细胞癌或人唾液腺样囊性癌非常有效。 4.我们用维纳里酮从TYS细胞中分离并鉴定了人TSC-22基因。(1)在体外和裸鼠中生长的人唾液癌细胞中TSC-22基因的下调引起了显着加速。 (2) TYS细胞中TSC-22蛋白的过表达导致抗癌药物(5-FU和(3) TSC-22基因由3个外显子组成，转录起始位点位于TATA盒样序列下游7bp和29bp处，包含转录因子(例如NF-)的假定结合位点。 kB、MyoD、AP-1、PU、C/EBP、p53、c-Myb、Sp1、NF1 或 Smad.5 转录因子。 TYS细胞中p21Waf1启动子中存在维纳里酮响应元件（Sp1-1和Sp1-2位点）。6．