骨肉瘤是儿童和青少年长骨上最常见的恶性肿瘤，致残率高、预后极差。在临床治疗中，骨肉瘤对化疗药物产生耐受是导致化疗失败的主要原因。高迁移率族蛋白B-1（HMGB1）是核内DNA结合蛋白，在基因转录重组修复以及细胞存活等方面发挥调控作用。应激条件下，HMGB1从核内转位至胞质，启动细胞存活机制即自噬的产生，介导肿瘤细胞的耐药性。因此HMGB1是克服耐药的一个潜在靶标。我国传统中医药学对骨肿瘤的治疗始于周代，活血化瘀、益气健脾是中医内治恶性骨肿瘤的基本配伍规律，并根据临床辨证辅以清热解毒、化湿、化痰、补肾等。本项目在前期基础上，以活血、清热和化湿等中药为研究对象，采用色谱分离和活性筛选相结合的方法，寻找具有抑制HMGB1作用、抑制细胞自噬、逆转骨肉瘤耐药活性的化合物，并在细胞和动物水平上阐明其作用机理。本项目为从中药中发现高效低毒、结构新颖具有药用价值的活性化合物，开发新型肿瘤逆转剂奠定基础。

Osteosarcoma is the most common malignant tumor of bone, frequently occurred in children and adolescents. Chemotherapy is the major treatment. Unfortunately, it often failed due to the development of drug resistance. High-mobility group box 1 (HMGB1) is a DNA binding protein that plays a key role in chromatin construction，gene transcription，recombination，DNA damage repair and cell death /survival. Upon cellular stresses，HMGB1 is translocated from nucleus to cytosol and induces autophagy，which eventually mediates cellular resistance to anti-cancer drugs. Thus，HMGB1 is becoming a potential target in tumor cells for overcoming drug resistance．Traditional Chinese medicine (TCM) has long history documentation on bone tumors therapy. The basic treatment rules in TCM are nourishing qi to invigorate spleen and promoting blood flow, combining with dissipating phlegm, dehygrosis or heat-clearing, and detoxicating according to clinic syndromes. On the basis of preliminary study, this project focuses on screening reversal agents from TCMs targeting HMGB1-mediated autophagy. Fractionated extracts and compounds from traditional medicine would be tested for their potential to inhibit HMGB1 activities, inhibit autophagy and reverse drug resistance in osteosarcoma. The results of this project will afford some useful reversal agents, giving a glimpse of the therapeutic value of TCM in this regards.