泛素-蛋白酶体系统已成为抗肿瘤药物的重要靶点。经美国FDA批准蛋白酶体抑制剂万可已应用于多发性骨髓瘤的治疗。但是万可以及多数目前报道的蛋白酶体抑制剂没有细胞选择性，在应用时难以避免产生一定的毒副效用。因此寻找细胞特异性强和毒副作用小的蛋白酶体抑制剂对于肿瘤的治疗具有重要价值。藤黄酸（GA）具有广泛的抗肿瘤作用，并经中国FDA批准用于临床肿瘤的治疗。在前期研究中证实，GA是一个典型的蛋白酶体抑制剂，其经过细胞内CYP2E1代谢后生成C9,C10-环氧藤黄酸发挥蛋白酶体抑制效应。由于细胞内CYP2E1水平决定了GA的蛋白酶体抑制效应，因此GA与Vel明显不同，其产生的蛋白酶体抑制具有细胞或组织特异性。本研究旨在探讨：(1)GA诱导蛋白酶体功能抑制发挥抗肿瘤效应是否具有脱靶效应,以明确GA抗肿瘤分子靶点;(2)GA介导的组织或细胞特异性蛋白酶体抑制的重要意义，以阐明GA不明显产生毒副作用的机理。

Ubiquitin-proteasome system is becoming an important drug target for cancer therapy. Bortezomib as the first specific proteasome inhibitor anticancer drug has been approved by US FDA for the treatment of multiple myeloma, but chemotherapeutics including proteasome inhibitors have severe side effects due to its non cell-specific effect, suggesting the need for discovery of novel proteasome inhibitors with no or low toxicity. It has been reported in both animal tumor models and clinical trials that GA efficiently inhibits tumor growth with minimal side effects, especially with little toxicity on immune and hemopoietic system. We have found that proteasome is a proteasome inhibitor which is metabolized to an active proteasome inhibitor by CYP2E1.Therefore, GA, not like bortezomib ,would lead to cell- or tissue-specific proteasome inhibition due to the specific distribution of CYP2E1 in the cell. The aim of this study is to investigate (1) whether GA exerts anti-cancer effect via proteasome inhibition without off-targets so as to illustrate GA's anti-cancer molecular target; (2) the importance of cell- or tissue-specific proteasome inhibition mediated by GA to further understand how GA induces low or none toxicity in cancer therapy.