中文版 | English
题名

SOD1抑制剂与阿霉素联合使用增强未分化状甲状腺癌的药物敏感性

其他题名
SOD1 INHIBITOR ATN-224 COMBINED WITH DOXORUBICIN ENHANCES DRUG SENSITIVITY IN ANAPLASTIC THYROID CANCER
姓名
姓名拼音
XU Jinyue
学号
12032624
学位类型
硕士
学位专业
071010 生物化学与分子生物学
学科门类/专业学位类别
07 理学
导师
张文勇
导师单位
南方科技大学医学院
外机构导师单位
sustech
论文答辩日期
2023-05-17
论文提交日期
2023-06-26
学位授予单位
南方科技大学
学位授予地点
深圳
摘要
  甲状腺癌是一种常见的癌症,在我国,甲状腺癌发病率为 4.8%且仍在逐年递增。未分化状甲状腺癌(anaplastic thyroid cancer, ATC)是一种起源于甲状腺滤泡上皮细胞的癌症,是所有甲状腺癌症类型当中最为罕见的一种类型,且具有较强的转移和侵袭能力,并且对常规的化疗药物都具有较强的耐药性。目前 ATC 并没有十分有效的治疗手段,人们迫切需要找到新的治疗靶点和治疗方案,来改善未分化状甲状腺癌的治疗效果。
  阿霉素是一种具有广泛抗癌谱的化疗药物,同时也是治疗未分化状甲状腺癌的主要指定化疗药物。然而,由于癌细胞产生耐药性等因素,大幅降低了癌细胞对阿霉素的敏感程度,疗效也大打折扣。目前,人们对这种现象的产生机制并没有明确的定论。本课题通过蛋白质组学质谱分析技术检测了两种未分化状甲状腺癌细胞系:HTC/C38505C,与正常甲状腺细胞系 Nthy-ori 3 相比蛋白质组水平的差异,我们发现两种 ATC 细胞系中,尤其是在 8505C 细胞系中,超氧化物歧化酶 1SOD1)的酶活性和蛋白表达量均异常升高。由于前期研究表明 SOD1 过表达可以增加癌细胞的抗药性,因此靶向抑制 SOD1 蛋白一定程度上有可能能够增强 ATC 对阿霉素的敏感程度,改善疗效。
  我们采用了一种 SOD1 蛋白的特异性抑制剂 ATN-224 联合阿霉素处理8505C 细胞。结果显示,ATN-224 与阿霉素加药处理之后,与单独阿霉素用药相比,8505C 细胞的活性和迁移能力均下降,Nrf2SOD1GPx1 蛋白的表达受到抑制。另外,PI3K/AKT 增殖信号通路受到抑制,Bad 蛋白以及 cleaved-caspase 3 蛋白表达量增加,诱导细胞凋亡。因此,ATN-224 能够十分有效地增强阿霉素对于 8505C 细胞的毒性作用。随后我们构建了nu/nu 小鼠皮下肿瘤模型,经过 ATN-224 联合阿霉素用药后,肿瘤生长受到显著抑制,而小鼠体重无明显变化,而单独用药组中的肿瘤生长与空白对照组并无显著区别。我们的研究发现 SOD1 抑制剂 ATN-224 联合阿霉素用药能够有效缓解 8505C 对于阿霉素的不敏感性,为未分化状甲状腺癌的治疗方案优化开辟了新方向。
其他摘要
      Thyroid cancer is a common cancer type. In China, the incidence rate of thyroid cancer is 4.8% and is still increasing. Anaplastic thyroid cancer(ATC), which is originated from thyroid follicular epithelial cells, is the rarest thyroid cancer subtype. It has strong metastatic and invasive abilities, and has strong resistance against traditional anti-cancer drugs. At present, there has no effective treatment for ATC. So there has a strong need to find new treatment targets and strategies, to improve ATC treatment effect.
       Doxorubicin(DOX), is known as a chemotherapy drug with a wide spectrum anticancer effect. Also, DOX is the main anticancer chemotherapy drug used for anaplastic thyroid cancer. However, because of the resistance in tumor cells, the therapeutic effect could be significantly reduced. Currently, there is no clear conclusion about how drug resistance occurs and what molecular mechanism underlies it. In our study, comparing with human normal thyroid cell line Nthy-ori 3, two ATC cell lines: HTC/C3 and 8505C were detected by proteomic mass spectrometry analysis technology. We found that the enzyme activity and expression level of superoxide dismutase 1(SOD1) was abnormally enhanced in ATC cell lines, especially in 8505C cells. Also, the previous studies have showed that the over expression of SOD1 contributed to the drug resistance in cancer cells. Therefore, targeting SOD1 could be a possible strategy to enhance the sensitivity of 8505C cells to DOX.
       We applied ATN-224, a specific inhibitor of SOD1 in 8505C combination treatment. The results showed that after ATN-224 and DOX treatment, comparing with DOX treated group, 8505C cell viability and migration ability were decreased. The expression levels of Nrf2, SOD1, GPx1 were inhibited. In addition, PI3K/AKT signaling pathway was inhibited, and the expression level of Bad and cleaved-caspase 3 were increased, leading to cell apoptosis. Therefore, combined with DOX, ATN-224 could effectively enhance the cytotoxic effect in 8505C cells. We also constructed a subcutaneous tumormodel in nu/nu mice. After ATN-224 and DOX combination treatment, the tumor growth was significantly inhibited, while the body weight of mice did not change significantly. Also, there was no significant change in tumor growth in the single drug treatment group. Our study found that combination of SOD1 inhibitor ATN-224 with doxorubicin could effectiverly enhance the sensitivity
of 8505C to doxoribucin. It opens up a new direction for the optimization of treatment options for anaplastic thyroid cancer.
关键词
其他关键词
语种
中文
培养类别
独立培养
入学年份
2020
学位授予年份
2023-06
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徐锦岳. SOD1抑制剂与阿霉素联合使用增强未分化状甲状腺癌的药物敏感性[D]. 深圳. 南方科技大学,2023.
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