硼替佐米
蛋白激酶B
药理学
化学
PI3K/AKT/mTOR通路
雷公藤醇
信号转导
细胞凋亡
癌症研究
多发性骨髓瘤
细胞生物学
生物
生物化学
免疫学
作者
Shuhan Jin,Bo Li,Bibo Zhang,Xuejie Gao,Xiaoli Jia,Li Xu,Shuaikang Chang,Ke Hu,Guanli Wang,Zhijian Xu,Ting Zhang,Dongli Song,Guangchao Yang,Xiaosong Wu,Hui Zhu,Cheng Huang,Yumeng Lu,Jumei Shi,Weiliang Zhu,Gege Chen
摘要
Multiple myeloma (MM) is characterized by excessive aggregation of B-cell-derived malignant plasma cells in the hematopoietic system of bone marrow. Previously, we synthesized an innovative molecule named dihydrocelastrol (DHCE) from celastrol, a triterpene purified from medicinal plant Tripterygium wilfordii. Herein, we explore the therapeutic properties and latent signal transduction mechanism of DHCE action in bortezomib (BTZ)-resistant (BTZ-R) MM cells. In this study, we first report that DHCE shows antitumor activities in vitro and in vivo and exerts stronger inhibitory effects than celastrol on BTZ-R cells. We find that DHCE inhibits BTZ-R cell viability by promoting apoptosis via extrinsic and intrinsic pathways and suppresses BTZ-R MM cell proliferation by inducing G0/G1 phase cell cycle arrest. In addition, inactivation of JAK2/STAT3 and PI3K/Akt pathways are involved in the DHCE-mediated antitumor effect. Simultaneously, DHCE acts synergistically with BTZ on BTZ-R cells. PSMB5, a molecular target of BTZ, is overexpressed in BTZ-R MM cells compared with BTZ-S MM cells and is demonstrated to be a target of STAT3. Moreover, DHCE downregulates PSMB5 overexpression in BTZ-R MM cells, which illustrates that DHCE overcomes BTZ resistance through increasing the sensitivity of BTZ in resistant MM via inhibiting STAT3-dependent PSMB5 regulation. Overall, our findings imply that DHCE may become a potential therapeutic option that warrants clinical evaluation for BTZ-R MM.
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