DCZ0814 induces apoptosis and G0/G1 phase cell cycle arrest in myeloma by dual inhibition of mTORC1/2

doi:10.2147/CMAR.S194202

	DCZ0814 induces apoptosis and G0/G1 phase cell cycle arrest in myeloma by dual inhibition of mTORC1/2
	Kong, Yuanyuan 1; Li, Bo 2; Chang, Shuaikang 1; Gao, Lu 1; Xu, Zhijian 2; He, Wan 1; Yang, Guang 1; Xie, Bingqian 1; Chen, Gege 1; Hu, Liangning 1
刊名	CANCER MANAGEMENT AND RESEARCH
	2019
卷号	11 页码:4797-4808
关键词	DCZ0814 multiple myeloma mTOR bone marrow microenvironment apoptosis
ISSN号	1179-1322
DOI	10.2147/CMAR.S194202
通讯作者	Zhu, Weiliang(wlzhu@simm.ac.cn) ; Shi, Jumei(shijumei@tongji.edu.cn)
英文摘要	Purpose: The present study investigates the effect of DCZ0814 in multiple myeloma (MM) cells, and determines the molecular mechanism of its antitumor activity against MM. Methods: The effects of DCZ0814 were evaluated in vitro using human MM cell lines (ARP1 and OCI-MY5) and in vivo in a murine xenograft MM model. Cell viability was measured with the CCK-8 assay and mitochondrial membrane potential (MMP) was assessed with the JC-1 dye. Apoptosis and cell cycle distribution were examined by flow cytometry. Inhibition of mTORC1 and mTORC2 was assessed by western blot analysis, and the synergistic effect of DCZ0814 and known MM drugs was assessed by calculating the combination index value, using the CalcuSyn software. Results: DCZ0814 effectively inhibited proliferation in MM cells, an effect that was associated with the induction of apoptosis, G0/G1 cell cycle arrest, MMP reduction and reactive oxygen species (ROS) generation. Meanwhile, DCZ0814 repressed the mTOR signaling via dual mTORC1/C2 inhibition and overcame the protective effect of the bone marrow (BM) microenvironment in myeloma cells. In addition, co-treatment with DCZ0814 and other anti-MM agents induced synergistic effects. Finally, the efficacy of the DCZ0814 treatment was confirmed in an MM xenograft mouse model. Conclusion: DCZ0814 exhibits potent anti-MM activity and abrogates the activation of the mTOR/Akt signaling pathway mediated by the BM stroma-derived cytokines. Our results provide a theoretical basis for the development of novel therapeutic strategies in MM using DCZ0814 as a natural product combination compound.
资助项目	National Natural Science Foundation of China[81570190] ; National Natural Science Foundation of China[81670194] ; National Natural Science Foundation of China[81529001] ; National Key Research and Development Program[2016 YFA0502301]
WOS关键词	NF-KAPPA-B ; BONE-MARROW ; SOLID TUMORS ; KINASE ; IDENTIFICATION ; CCI-779 ; TORC1/2 ; GROWTH ; RICTOR
WOS研究方向	Oncology
语种	英语
出版者	DOVE MEDICAL PRESS LTD
WOS记录号	WOS:000469765300001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289618]
专题	中国科学院上海药物研究所
通讯作者	Zhu, Weiliang; Shi, Jumei
作者单位	1.Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Dept Hematol,Tongji Univ Canc Ctr, Shanghai 200072, 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
推荐引用方式 GB/T 7714	Kong, Yuanyuan,Li, Bo,Chang, Shuaikang,et al. DCZ0814 induces apoptosis and G0/G1 phase cell cycle arrest in myeloma by dual inhibition of mTORC1/2[J]. CANCER MANAGEMENT AND RESEARCH,2019,11:4797-4808.
APA	Kong, Yuanyuan.,Li, Bo.,Chang, Shuaikang.,Gao, Lu.,Xu, Zhijian.,...&Shi, Jumei.(2019).DCZ0814 induces apoptosis and G0/G1 phase cell cycle arrest in myeloma by dual inhibition of mTORC1/2.CANCER MANAGEMENT AND RESEARCH,11,4797-4808.
MLA	Kong, Yuanyuan,et al."DCZ0814 induces apoptosis and G0/G1 phase cell cycle arrest in myeloma by dual inhibition of mTORC1/2".CANCER MANAGEMENT AND RESEARCH 11(2019):4797-4808.