目前对逆转人骨肉瘤化疗耐药的研究，大多集中于寻找高效且低毒的逆转剂使耐药肿瘤对化疗复敏，虽投入了大量人力、物力但收效甚微。因此申请者不再重点关注人骨肉瘤化疗耐药形成后的治疗策略，而是聚焦于研究如何克服化疗耐药的产生，即在化疗初期便抑制肿瘤耐药的发生。前期研究表明，ATF4和GRP78是介导耐药发生的重要靶点，高表达ATF4并抑制GRP78能在化疗初期有效阻碍化疗耐药的产生。申请者发现从酸浆提取的睡茄内酯类物质Physagulin C既能上调ATF4又可以抑制GRP78表达，并能提高耐药骨肉瘤对阿霉素的敏感性。酸浆是我国的传统中药材具有清热解毒、利咽化痰、利湿除热的功能，其功效符合中医治疗骨肉瘤的用药策略。近年来研究人员发现酸浆中的睡茄内酯类成分具有抗肿瘤的活性；申请者将从酸浆中提取睡茄内酯类物质进行研究，以期寻找出能克服人骨肉瘤耐药产生的活性单体，为酸浆用于骨癌治疗的新用途提供理论基础。

The current studies of anti-chemoresistance in osteosarcoma focus on finding safe reversal agents, lots of works have been done but the results are poor. Therefore, we search for a novel strategy to prevent drug-resistance occur in the initial treatment with chemotherapy. Previous studies indicated that ATF4 and GRP78 which are important targets mediate the development of drug-resistance. ATF4 up-regulation combines with GRP78 inhibition prevents chemoresistance development induced by doxorubicin at the beginning of the incubation. We found that a kind of withanolides: Physagulin C extracted from Physalis alkekengi var.franchetii (Mast.) Makino facilitates ATF4 expression and suppresses GRP78 up-regulation, and increases the sensitivity of resistant osteosarcoma to doxorubicin. Physalis alkekengi var.franchetii (Mast.) Makino is traditional Chinese medicine, it can be clearing heat and detoxicating, relieving sore-throat, eliminating damp-heat and promoting urinary discharge. Recently, scientists found Physalis alkekengi var.franchetii (Mast.) Makino has antineoplastic effect, the basis is withanolides. We will isolate withanolides from Physalis alkekengi var.franchetii (Mast.) Makino, test their promotion on ATF4 or inhibitory effect on GRP78, and study their mechanisms regarding preventing the development of chemoresistance in osteosarcoma. This study will provide new strategy and research foundation for Physalis alkekengi var.franchetii (Mast.) Makino in the therapy of osteosarcoma.