小细胞肺癌由于恶性程度高，难以手术治疗，主要以化疗为主，但目前化疗药物少且毒副作用大，开发毒副作用小的新型靶向性药物具有重大的临床意义。WA是从海洋微生物中分离的新化合物，前期研究证明其有针对性的抗小细胞肺癌作用，疗效与顺铂相当，但毒副作用远小于顺铂，初步完成了临床前研究，成药前景良好。全基因组表达芯片结果显示WA能使NCI-H446细胞的AKR1C1基因表达下降122倍，细胞中AKR1C1蛋白表达也明显下调，过表达该基因能逆转WA的作用。AKR1C1为Ⅱ相解毒酶基因，在多种肿瘤中高表达，不仅与肿瘤耐药有关，近年来有研究表明其高表达能抑制凋亡诱导因子生成，促进肿瘤细胞的生长和转移。目前临床尚无以降低AKR1C1表达为靶标的药物。本课题拟从分子水平探讨WA主要通过Nrf2/ARE途径靶向作用AKR1C1基因，从而引起细胞凋亡，抑制增殖和迁移，旨在为小细胞肺癌的化疗提供新的作用靶点和作用药物。

1， Small cell Lung cancer is mainly treated with chemotherapy since its high malignant degree which is hard to be treated with surgery operations. However, the medicine for chemotherapy is quite limited. Consequently, there is a great clinical significance to develop drugs with totally new mechanism. Wentilactone A is a new compound which is extracted from marine microorganism. it induces growth inhibition of small cell lung cancer cells in vivo and in vitro. Moreover, its effects is equal to cisplatin and even better than cyclophosphamide while the side effects is much less than cisplatin. Pre-clinical trials have all proved that it can be the anti-tumor drug candidate for small cell lung cancer. The result of gene chip suggests that the AKR1C1 mRNA expression of NCI-H446 cells could be decreased by 122 times after Wentilactone A treatment. Moreover the protein expression of AKR1C1 is also dcreased as follow, and overwxpression of AKR1C1 could reverse the effect of Wentilactone A. AKR1C1 is a Phase Ⅱ enzyme. The expression of AKR1C1 gene always maintains at high level in many cancers, which may related on drug resistance of these cancers. And recent reports suggested that high level of AKR1C1 decreased the expression of AIF, and promoted cell growth and migration. However, there is no dugs that can effectively decrease the expression of AKR1C1. This study will further approve that Wentilactone A could decrease the expression of AKR1C1 mainly through the Nrf2/ARE signalling pathway, thereby causing the cell apoptosis, cell growth inhibition and migration inhibitory of small cell lung cancer cells. This research will provide a new target for the chemotherapy of small cell lung cancer.