中药活性成分水飞蓟宾通过靶向TrxR1的抗卵巢癌药理机制的研究

Silibinin is the dried mature fruit of Silymarin. Silibinin as a clinical liver protective drug, also have good anti-tumor effect. TrxR1 is the critical enzyme in regulating the redox balance and ROS in vivo. Regulating the balance of oxidative stress to induce tumor cell apoptosis that is an important anti-tumor strategy. Our previous studies found that silibinin could bind directly to TrxR1, along with inhibition of TrxR1 activity, and induce apoptosis of ovarian cancer cells through activation of ROS level. At the same time, we also found that the expression and activity of TrxR1 in human ovarian cancer cells are significantly increased. Therefore, we hypothesized that silibinin selectively kills ovarian cancer cells by targeting of TrxR1 to increase ROS generation. The project plans to identify TrxR1 is the effectively direct target of silibinin at the cellular and molecular levels, and clarify the specific molecular mechanism of anti-tumor by inhibiting the TrxR1 protein. Furthermore, we will verify the effect of silibinin against ovarian cancer at animal level, and testify the effect on the enhancement of chemosensitivity towards fisrt-line chemotherapeutic agents in combination with Silibinin. This research project will make a valuable contribution to the evidence base about TrxR1 as a effectively direct target of silibinin, approach to clarify the molecular mechanism of silibinin induced apoptosis, and provide a novel target for the treatment of ovarian cancer

水飞蓟宾为菊科植物水飞蓟的干燥成熟果实，作为临床保肝药物，同时具有良好的抗肿瘤 活性。TrxR1是体内调节氧化还原平衡和ROS的重要蛋白，调节氧化应激平衡诱导肿瘤细胞凋亡 是一种重要的抗肿瘤策略。我们前期研究发现水飞蓟宾能够直接结合TrxR1并抑制其酶活性， 激活氧化应激，选择性的诱导卵巢癌细胞凋亡。同时，我们也发现人卵巢癌细胞中TrxR1的表 达和活性都明显上升。因此，我们推测水飞蓟宾是通过抑制TrxR1活性，上调细胞中ROS水平来 诱导卵巢癌细胞凋亡。本项目拟在细胞和分子层面上确证TrxR1为水飞蓟宾的直接有效分子靶 点，并阐明其抑制TrxR1后抗肿瘤的具体分子作用机制；动物层面验证水飞蓟宾的抗卵巢癌作 用，并联合临床化疗药物考察水飞蓟宾的增敏效果。本项目将确证TrxR1为水飞蓟宾的直接有 效作用靶点，阐明水飞蓟宾抗卵巢癌的分子机制，提出TrxR1可以成为卵巢癌治疗的新靶点。

卵巢癌是临床上妇科疾病中最致命的恶性肿瘤，被称为“沉默的杀手”，五年生存率不足40%。水飞蓟宾为菊科植物水飞蓟果实提取物，作为临床保肝药物，同时具有良好的抗肿瘤活性。本研究紧紧围绕卵巢癌和水飞蓟宾开展，阐明了水飞蓟宾增敏其他抗肿瘤药物（一线化疗药物顺铂和紫杉醇、中药抗肿瘤药物姜黄素及其光敏剂维替泊芬）的药理活性及其相关药理机制。本研究发现水飞蓟宾能够增敏一线化疗药物顺铂和紫杉醇、中药提取物姜黄素等对卵巢癌细胞的抗肿瘤活性，跨越顺铂的耐药机制，提高卵巢癌的治疗效果；并通过激活卵巢癌细胞内的ROS水平，抑制卵巢癌细胞TrxR1的表达水平，诱导细胞的死亡。此外，本研究还惊喜的发现水飞蓟宾的护肝功效还能有效降低化疗药物诱导的肝毒性。基于此，我们进一步拓展了水飞蓟宾与光敏剂维替泊芬的联合用药。我们的实验数据表明，水飞蓟宾能够显著提高维替泊芬对卵巢癌的光动力学治疗效率。我们的实验结果表明，水飞蓟宾是通过抑制TrxR1 活性上调卵巢癌细胞中ROS 水平来增敏化疗药物或光动力学治疗药物的抗卵巢活性，并降低化学药物诱导的肝毒性；在卵巢癌治疗中起到增敏护肝的作用，为卵巢癌的治疗提供新的思路和策略。