大蒜新素纳米控释剂重塑卵巢癌炎性微环境抗肿瘤机制研究

Ovarian cancer is the most deadly cancer of female reproductive system, The 5-year survival rate of patients with advanced ovarian caner is only between 20%-30%. Therefore, it would be great significance to explore new and effective therapeutic methods which will dramatically increase the survival rate. Our experiment reveals that allicin can significantly inhibit ovarian cancer cell growth and induce apoptosis. Further studies indicate that via JNK signaling pathway, allicin can active the Bcl-2 family to stimulate the mitochondrial mediated pathway, which leads to induction of apoptosis. Based of the characteristics of allicin, We hypothesize that anti-tumor mechanism of allicin may be related to inhibition of tumor-associated inflammation as well as microenvironment of tumor remodeling. The main active ingredient of allicin is allitridin. This research is to prepare the allitridin nanoparticles controlled-release suppository for Intravenous medication, combining with confocal laser, luciferase reporter gene recombinant method to announce the vital action of signaling pathway of TLRs/MyD88/NF-κB in building of inflammatory microenvironment of ovarian cancer. At the meantime, with the in vivo and in vitro experiment, we comprehend the action of allitridin nanoparticles controlled-release suppository and its mechanism of action in remodeling of ovarian cancer microenvironment, which lays a solid theoretical foundation for its clinical application.

卵巢癌是女性生殖系统致死率最高的肿瘤，晚期卵巢癌患者5年生存率仅为20％ 一30％。因此，探索新的有效的治疗对策对提高卵巢癌患者生存率具有重要意义。我们的实验表明大蒜素可显著抑制卵巢癌细胞的生长，诱导细胞凋亡。进一步研究发现大蒜素通过JNK信号通路，激活Bcl-2家族，激发线粒体介导途径，诱导细胞凋亡。鉴于大蒜素作用特点，我们提出假说：大蒜素抗肿瘤机制可能与其抑制肿瘤相关性炎症、重塑肿瘤微环境相关。大蒜素的主要有效成分是大蒜新素。本研究拟制备静脉给药的大蒜新素纳米控释剂，采用激光共聚焦、荧光素酶报告基因重组体方法，揭示TLRs/MyD88/NF-κB信号通路在卵巢癌炎性微环境构建中的作用。同时，通过体内外实验明确大蒜新素纳米控释剂重塑卵巢癌微环境的作用及作用机制，为大蒜新素纳米控释剂在临床的应用奠定坚实的理论基础。

卵巢癌是女性生殖系统致死率最高的肿瘤，探索新的有效的治疗对策对提高卵巢癌患者生存率具有重要意义。本项目探讨大蒜新素纳米控释剂抑制肿瘤相关性炎症，重塑肿瘤微环境的作用模式和作用通路。研究结果表明：（1）成功构建符合药学研究标准的大蒜新素纳米控释剂(Alltride-NPs)。（2）大蒜新素纳米控释剂可显著抑制人卵巢癌SKOV3细胞的生长，诱导凋亡。（3）通过Westen blotting法检测IRAK-4、TRIF水平和cJun磷酸化情况；荧光定量PCR（RT—PCR）测定TLR4及MyD88的表达；ELISA法检测IL-8、IL-6、VEGF、MCP-1因子含量。结果提示：大蒜新素纳米控释剂下调TLR4及MDY88的表达；与对照组相比，IRAK-4、TRIF表达也有不同程度的下降；IL-8、IL-6、VEGF、 MCP-1炎性因子分泌减少。（4）通过免疫荧光，激光共聚焦方法显示大蒜新素纳米控释剂抑制了NF-κB的核转位。（5）体内外实验还显示，大蒜新素纳米控释剂能抑制裸鼠皮下移植瘤的生长，与紫杉醇具有明确的协同作用，核转位阳性物质表达下降，血清中IL-8、IL-6、VEGF、MCP-1因子分泌减少。大蒜新素纳米控释剂重塑卵巢癌微环境的作用及作用机制与抑制NF-κB信号通路相关，为大蒜新素纳米控释剂在临床的应用奠定坚实的理论基础。