海洋来源先导化合物Asperolide A 靶向乳腺癌细胞和破骨细胞的“恶性循环”途径抗乳腺癌骨转移分子机制研究

乳腺癌是全球女性发病率最高的恶性肿瘤，乳腺癌骨转移更是其主要致死原因。乳腺癌细胞分泌的细胞因子可以促进破骨细胞分化成熟，破骨细胞活动增强可释放更多的因子刺激乳腺癌细胞的增殖，如此形成一个“恶性循环”，是导致骨转移的主要原因。目前临床上常用的双磷酸盐通过抑制破骨细胞活性治疗乳腺癌骨转移，但疗效有限，尚未有靶向“恶性循环”途径同时抑制乳腺癌增值和骨转移的药物。Asperolide A是从海洋微生物提取的新化合物，前期在863课题资助下发现其在体内外可能通过PI3K/AKT/mTOR信号通路靶向“恶性循环”途径同时抑制乳腺癌及骨转移。本课题拟通过干扰RNA，免疫荧光，qRT-PCR等技术明确其同时抑制乳腺癌增殖和破骨细胞活性的分子机制，通过高通量反向虚拟筛选，薛定谔对接算法等技术确定其作用靶点，与常用药物比较其在体内的药效，通过本研究为临床乳腺癌骨转移治疗提供新的药物作用靶点和候选药物。

Breast cancer is the highest incidence rate among women with malignant tumors worldwide. Bone metastasis is the main factor causing the death. Cytokines secreted by breast cancer cells can promote osteoclast differentiation and maturation. Increased osteoclast activity can release more factors to stimulate the proliferation of breast cancer cells conversely. Thus a vicious circle is formed. Bisphosphonates are used to treat breast cancer bone metastasis by inhibiting osteoclast activity. There is no drug to inhibit development of breast cancer and breast cancer induced osteolysis. Asperolide A, extracted from marine microorganisms, targets breast cancer induced "vicious circle" and inhibits breast cancer induced osteolysis via PI3K /AKT/mTOR signal pathway in vivo and vitro. We intend to clarify the inhibition mechanism of Asperolide A on breast cancer proliferation and osteoclast formation and function by siRNA, immunofluorescence, qRT-PCR and other molecular biology technologies, and find the target by high-throughput reverse virtual screening technology, Schrodinger docking algorithm and other technologies. The purpose of this study is to provide new candidate drugs with certain targets for breast cancer induced osteolysis.