Co-inhibition of BET and NAE enhances BIM-dependent apoptosis with augmented cancer therapeutic efficacy
文献类型：期刊论文
| 作者 | Zhang, Qian2,3; Wu, Qian2,3; Huan, Xia-Juan3; Song, Shan -Shan3; Bao, Xu-Bin3; Miao, Ze- Hong1,2,3; Wang, Ying-Qing1,2,3
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| 刊名 | BIOCHEMICAL PHARMACOLOGY
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| 出版日期 | 2024-05-01 |
| 卷号 | 223页码:17 |
| 关键词 | BET inhibitor NAE inhibitor BIM Apoptosis Combination therapy |
| ISSN号 | 0006-2952 |
| DOI | 10.1016/j.bcp.2024.116198 |
| 通讯作者 | Miao, Ze- Hong(zhmiao@simm.ac.cn) ; Wang, Ying-Qing(yqwang@simm.ac.cn) |
| 英文摘要 | Agents that inhibit bromodomain and extra-terminal domain (BET) proteins have been actively tested in the clinic as potential anticancer drugs. NEDD8-activating enzyme (NAE) inhibitors, represented by MLN4924, target the only activation enzyme in the neddylation pathway that has been identified as an attractive target for cancer therapy. In this study, we focus on the combination of BET inhibitors (BETis) and NAE inhibitors (NAEis) as a cancer therapeutic strategy and investigate its underlying mechanisms to explore and expand the application scope of both types of drugs. The results showed that this combination synergistically inhibited the proliferative activity of tumor cells from different tissues. Compared to a single drug, combination therapy had a weak effect on cycle arrest but significantly enhanced cell apoptosis. Furthermore, the growth of NCI-H1975 xenografts in nude mice was significantly inhibited by the combination without obvious body weight loss. Research on the synergistic mechanism demonstrated that combination therapy significantly increased the mRNA and protein levels of the proapoptotic gene BIM. The inhibition and knockout of BIM significantly attenuated the apoptosis induced by the combination, whereas the re-expression of BIM restored the synergistic effects, indicating that BIM induction plays a critical role in mediating the enhanced apoptosis induced by the co-inhibition of BET and NAE. Together, the enhanced transcription mediated by miR-17-92 cluster inhibition and reduced degradation promoted the increase in BIM levels, resulting in a synergistic effect. Collectively, these findings highlight the need for further clinical investigation into the combination of BETi and NAEi as a promising strategy for cancer therapy. |
| WOS关键词 | NEDD8-ACTIVATING ENZYME ; PROTEIN NEDDYLATION ; BROMODOMAIN ; DISCOVERY ; PROLIFERATION ; AUTOPHAGY ; MIR17-92 ; MLN4924 ; SYSTEM ; FAMILY |
| 资助项目 | National Natural Science Foundation of China[82073865] ; National Natural Science Foundation of China[81773764] ; Science and Technology Commission of Shanghai Municipality[20ZR1468100] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0320231010] ; State Key Laboratory of Drug Research |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001228532800001 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/311066]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Miao, Ze- Hong; Wang, Ying-Qing |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Qian,Wu, Qian,Huan, Xia-Juan,et al. Co-inhibition of BET and NAE enhances BIM-dependent apoptosis with augmented cancer therapeutic efficacy[J]. BIOCHEMICAL PHARMACOLOGY,2024,223:17. |
| APA | Zhang, Qian.,Wu, Qian.,Huan, Xia-Juan.,Song, Shan -Shan.,Bao, Xu-Bin.,...&Wang, Ying-Qing.(2024).Co-inhibition of BET and NAE enhances BIM-dependent apoptosis with augmented cancer therapeutic efficacy.BIOCHEMICAL PHARMACOLOGY,223,17. |
| MLA | Zhang, Qian,et al."Co-inhibition of BET and NAE enhances BIM-dependent apoptosis with augmented cancer therapeutic efficacy".BIOCHEMICAL PHARMACOLOGY 223(2024):17. |
入库方式： OAI收割
来源：上海药物研究所
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