Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma
文献类型：期刊论文
| 作者 | Gao, Minjie3; Li, Bo2; Sun, Xi3; Zhou, Yunfei2; Wang, Yingcong3; Tompkins, Van S.4; Xu, Zhijian2 ; Indima, Nekitsing5; Wang, Houcai3; Xiao, Wenqin3
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| 刊名 | THERANOSTICS
 |
| 出版日期 | 2017 |
| 卷号 | 7期号:15页码:3690-3699 |
| 关键词 | Multiple Myeloma DCZ3301 antitumor activities synergistic cytotoxicity |
| ISSN号 | 1838-7640 |
| DOI | 10.7150/thno.18345 |
| 文献子类 | Article |
| 英文摘要 | We synthesized a novel aryl-guanidino compound, DCZ3301, and found that it has potent cytotoxicity against multiple human cancer cell lines. The anticancer activity was most potent against multiple myeloma (MM). DCZ3301 induced cytotoxicity in MM cell lines, as well as patient myeloma cells, in part by decreasing mitochondrial membrane potential to induce apoptosis. In contrast, DCZ3301 had no cytotoxic effect on normal cells. DCZ3301 also inhibited cell cycling and caused a G2/M accumulation that corresponded with downregulation of Cdc25C, CDK1, and Cyclin B1. DCZ3301 retained its activity against MM cells in the presence of exogenous cytokines (IL-6 or VEGF) or bone marrow stromal cells (BMSCs) and reduced activity of multiple signaling pathways (STAT3, NF kappa B, AKT, ERK1/2) in MM but not normal cells. The STAT3 pathway played an important role in modulating DCZ3301-mediated cytotoxicity. Knockdown of STAT3 using siRNA in MM cells enhanced DCZ3301-induced cytotoxicity, whereas overexpression of STAT3 in MM cells partially protected them from apoptosis. In addition, DCZ3301 inhibited VEGF and IL-6 secretion in a dose-dependent fashion in a co-culture of MM cells and BMSCs. Combining DCZ3301 with bortezomib induced synergistic cytotoxicity in MM cell lines and primary MM cells. Finally, in vivo efficacy of DCZ3301 was confirmed in an MM xenograft mouse model. Together, these results provide a rationale for translation of this small-molecule inhibitor, either alone or in combination, to the clinic against MM. |
| WOS关键词 | MARROW STROMAL CELLS ; BONE-MARROW ; ANTITUMOR-ACTIVITY ; TRANSPLANTATION ; INHIBITOR ; APOPTOSIS ; GROWTH ; BORTEZOMIB ; RESISTANCE ; SORAFENIB |
| 资助项目 | National Natural Science Foundation of China[81372391] ; National Natural Science Foundation of China[81570190] ; National Natural Science Foundation of China[81529001] ; National Natural Science Foundation of China[81302699] ; National Natural Science Foundation of China[81602515] ; National Natural Science Foundation of China[31271496] ; National Natural Science Foundation of China[81600174] ; National Natural Science Foundation of China[81300443] |
| WOS研究方向 | Research & Experimental Medicine |
| 语种 | 英语 |
| WOS记录号 | WOS:000408444200006 |
| 出版者 | IVYSPRING INT PUBL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275700]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Tao, Yi; Zhu, Weiliang; Shi, Jumei |
| 作者单位 | 1.Tongji Univ, Coll Life Sci & Technol, Shanghai 200092, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 3.Tongji Univ, Shanghai Peoples Hosp 10, Sch Med, Canc Ctr,Dept Hematol, 301 Yanchang Rd, Shanghai 200072, Peoples R China; 4.Iowa State Univ, Biochem Biophys & Mol Biol Dept, Ames, IA USA; 5.Tongji Univ, Shanghai Peoples Hosp 10, Sch Med, Dept Radiol, Shanghai 200072, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Gao, Minjie,Li, Bo,Sun, Xi,et al. Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma[J]. THERANOSTICS,2017,7(15):3690-3699. |
| APA | Gao, Minjie.,Li, Bo.,Sun, Xi.,Zhou, Yunfei.,Wang, Yingcong.,...&Shi, Jumei.(2017).Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma.THERANOSTICS,7(15),3690-3699. |
| MLA | Gao, Minjie,et al."Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma".THERANOSTICS 7.15(2017):3690-3699. |
入库方式： OAI收割
来源：上海药物研究所
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