【摘要】 无机砷是环境致癌剂,砷暴露可导致包括癌症在内的多种疾病高发。但一些砷化合物如三氧化二砷(ATO)却可以有效治疗急性早幼性白血病等多种癌症。肿瘤抑制基因p53在介导癌症治疗中具有重要作用,但p53基因在ATO治疗中的作用机制尚不完全明了。模式生物秀丽线虫只具有单个p53基因,是研究机体p53对DNA损伤和细胞周期调控作用的良好模型。以gld-1(q485)线虫突变体为对象,研究ATO对其生殖腺肿瘤样增殖的影响,结果表明,ATO处理延长了gld-1(q485)突变体的寿命,抑制了生殖腺的肿瘤样增殖。进一步的研究表明,ATO处理抑制线虫生殖细胞增殖,并具有显著的剂量效应和时间效应;ATO处理还诱导了线虫生殖细胞凋亡。利用线虫CEP-1/p53基因突变品系,结合RNAi基因敲除技术,发现ATO诱导了不依赖于CEP-1/p53的生殖细胞周期停滞和依赖于CEP-1/p53的细胞凋亡。更多还原

【Abstract】 Inorganic arsenic has been shown as an environmental carcinogen, exposure to arsenic can resulted in high incidence of multiple diseases including cancer. Paradoxically, several arsenic compounds such as arsenic trioxide have been used effectively to treat promyelocytic leukaemia and other solid tumors. It has been shown that the tumor suppressor p53 plays important roles in cancer therapy. However, the roles of p53 on the treatment effects of ATO are still uncertain. The nematode Caenorhabditis elegans has been shown as a good model for studying the regulative effects of p53 on DNA damage and cell cycle because it has only a single p53-like gene cep-1. In the present study, the therapeutic effects of ATO on the gonad tumorous growth were studied using gld-1(q485) mutated worms. The results presented here indicated that ATO treatment extended the lifespan of gld-1(q485) mutants and inhibited tumorous growth of the gonad. ATO treatment induced cell cycle arrest in a dose-and time-dependent manner. It was also found that ATO treatment resulted in germline apoptosis in worms of N2 and gld-1(q485) mutants. By using worm strains carrying mutated cep-1 alleles plus RNAi double gene knockout, it was found that ATO exerted its antitumor activity on gld-1(q485) mutants through the induction of cell cycle arrest in a CEP-1/p53-independent manner and germline apoptosis in a CEP-1/p53-dependent manner.更多还原