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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.用维司力农处理人口腔鳞癌细胞系(BHY、HN：p53野生型(外显子4-9))和人涎腺癌细胞系(HSG、HSG-AZA1、HSG-AZA3：P53野生型；TYS：P53密码子281~lt；Asp→hls&gt；)，均出现细胞生长抑制和G1期停滞，其中p21^&lt、waf1&gt、p27^&lt、kip1&gt和tsc-22基因表达下调。荷瘤裸鼠口服维司力农后，肿瘤生长受到明显抑制，向角质形成细胞和腺泡细胞的分化也受到明显抑制。维司纳酮对口腔鳞状细胞癌或涎腺腺样囊性癌有很好的治疗效果。我们从经维司力农处理的TYS细胞中分离并鉴定了人TSC-22基因。(1)在体外培养和裸鼠体内生长的人涎腺癌细胞中，TSC-22基因的下调导致肿瘤生长明显加速，而该基因的上调显著抑制了非锚定生长。(2)TSC-22蛋白在TYS细胞中的过表达导致抗癌药物(5-FU和CDDP)或辐射诱导细胞凋亡。(3)TSC-22基因由3个外显子组成。转录起始点位于TATA盒类序列下游7bP和29bP。TSC-22启动子区域含有与转录因子如核因子-kB、MyoD、AP-1、PU、C/EBP、P53、c-Myb、Sp1、NF1或Smad5的可能结合位点。SP1和SP3转录因子与p21Waf1启动子中存在的维司力农反应元件(Sp1-1和Sp1-2位点)结合。Vesnarinone诱导TYS细胞组蛋白高乙酰化。