激素难治性前列腺癌耐药相关的炎症机制及小分子天然化合物的干预研究

以紫杉醇为首选的化疗是治疗激素难治性前列腺癌(HRPC)的主要手段。但约50%患者治疗后产生化疗抵抗，尚无有效的逆转策略。HRPC耐药除经典途径外，炎症因子参与的耐药机制备受关注，靶向炎症因子介导的信号成为克服耐药新的策略。我们构建的紫杉醇多药耐药前列腺癌细胞中转运蛋白MRP2、受体酪氨酸激酶IGF-1R的高表达与促炎因子IL1、IL6的异常高表达密切相关。筛选得到的具有抗炎活性的小分子天然化合物，通过显著下调耐药细胞IL-6表达、增加药物蓄积、提高化疗药物的敏感性。本课题通过研究炎症因子及其信号通路在HRPC耐药过程中的表达与调控规律、炎症因子的表达与耐药相关蛋白表达的对应关系，揭示炎症因子参与HRPC耐药的发生机制；并通过对具有抗炎活性的天然小分子化合物在逆转HRPC耐药中的应用进行体内外实验，研究其逆转耐药的机制，为从抗炎角度寻找HRPC耐药逆转剂奠定研究基础。

Docetaxel is the standard of care in men with hormone-resistant prostate cancer (HRPC). However, ~50% of patients do not respond to Docetaxel and are exposed to significant toxicity without direct benefit. Few therapeutic options are available. In?ammatory response emerges as a novel mechanism for chemotherapy resistance in addition to the typical multidrug resistance. Inhibiting in?ammatory cytokines is implicated in enhancement of chemosensitivity. We established paclitaxel-resistant cells PC3/Tax from parent PC-3. Microarray analysis revealed that expression levels of mrp2, encoding for a MRP2 transpoter, and insulin-like type I growth factor receptor (IGF-IR) genes were positively correlated with IL1 and IL6 in PC3/Tax cells. Treatment of resistant cells with small natural chemicals with anti-inflammatory activity resulted in a significant decreased IL6, enhanced accumulation of Rh123 in cells, subsequently led to restoration of docetaxel sensitivity. The present study is designed to investigate the role of in?ammatory cytokines in the development of drug-resistance in PCa, and identify the mechanisms by which IL1 and IL6 regulate the expressions of MRP2 and IGF-IR in resistant cells. Finally, reversal effects of anti-inflammatory natural chemicals on drug resistance will be examined in vitro and in vivo. The finding of this study will provide evidence that IL1 and IL6 play an important role in the development of drug resistance, and anti-inflammatory chemicals potentially reverse chemotherapy resistance in HRPC.