Dual inhibition of mTORC1/2 by DCZ0358 induces cytotoxicity in multiple myeloma and overcomes the protective effect of the bone marrow microenvironment
文献类型：期刊论文
| 作者 | Gao, Lu2; Li, Bo1; Yang, Guang2; Liu, Peng1; Lan, Xiucai2; Chang, Shuaikang2; Tao, Yi2; Xu, Zhijian2 ; Xie, Bingqian2; Sun, Xi2
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| 刊名 | CANCER LETTERS
 |
| 出版日期 | 2018 |
| 卷号 | 421页码:135-144 |
| 关键词 | mTOR Multiple myeloma Bone marrow microenvironment Apoptosis |
| ISSN号 | 0304-3835 |
| DOI | 10.1016/j.canlet.2018.02.009 |
| 文献子类 | Article |
| 英文摘要 | Interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment promotes the proliferation, survival and chemoresistance of MM. The mTOR pathway plays a key role in these undesirable BM microenvironment-mediated events. We synthesized a novel alkaloid compound, DCZ0358, that effectively inhibits mTOR signaling via dual mTORC1/2 inhibition and exhibits potent anti MM activity in cultured and primary MM cells, as well as a MM xenograft model but has little effect on normal cells. Importantly, we show that this compound can block the BM stromal cell-mediated activation of mTOR/Akt signaling and antagonizes the protective effect of the BM microenvironment. Moreover, DCZ0358 abrogates the bortezomib-triggered activation of Akt, leading to the synergism of DCZ0358 and bortezomib in MM cells. Taken together, our results provide the proof-of-concept for clinical evaluation of DCZ0358, alone or in combination, as an anti-MM agent in MM therapy. (C) 2018 Elsevier B.V. All rights reserved. |
| WOS关键词 | PHOSPHATIDYLINOSITOL 3-KINASE/AKT ; HEMATOLOGICAL MALIGNANCIES ; MAMMALIAN TARGET ; AKT KINASE ; IN-VITRO ; CELLS ; CANCER ; RAPAMYCIN ; PATHWAYS ; APOPTOSIS |
| 资助项目 | National Natural Science Foundation of China[81570190] ; National Natural Science Foundation of China[81529001] ; National Natural Science Foundation of China[81670194] ; National Natural Science Foundation of China[81573350] |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:000428830700018 |
| 出版者 | ELSEVIER IRELAND LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272320]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Zhu, Weiliang; Shi, Jumei |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.Tongji Univ, Shanghai Peoples Hosp 10, Dept Hematol, Sch Med, 301 Yanchang Rd, Shanghai 200072, Peoples R China; 3.Tongji Univ, Canc Ctr, Shanghai 200092, Peoples R China |
| 推荐引用方式 GB/T 7714 | Gao, Lu,Li, Bo,Yang, Guang,et al. Dual inhibition of mTORC1/2 by DCZ0358 induces cytotoxicity in multiple myeloma and overcomes the protective effect of the bone marrow microenvironment[J]. CANCER LETTERS,2018,421:135-144. |
| APA | Gao, Lu.,Li, Bo.,Yang, Guang.,Liu, Peng.,Lan, Xiucai.,...&Shi, Jumei.(2018).Dual inhibition of mTORC1/2 by DCZ0358 induces cytotoxicity in multiple myeloma and overcomes the protective effect of the bone marrow microenvironment.CANCER LETTERS,421,135-144. |
| MLA | Gao, Lu,et al."Dual inhibition of mTORC1/2 by DCZ0358 induces cytotoxicity in multiple myeloma and overcomes the protective effect of the bone marrow microenvironment".CANCER LETTERS 421(2018):135-144. |
入库方式： OAI收割
来源：上海药物研究所
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