Dihydrocelastrol exerts potent antitumor activity in mantle cell lymphoma cells via dual inhibition of mTORC1 and mTORC2

doi:10.3892/ijo.2018.4438

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	Dihydrocelastrol exerts potent antitumor activity in mantle cell lymphoma cells via dual inhibition of mTORC1 and mTORC2
	Xie, Yongsheng 2; Li, Bo 1; Bu, Wenxuan 2; Gao, Lu 2; Zhang, Yong 1; Lan, Xiucai 2; Hou, Jun 2; Xu, Zhijian1 ; Chang, Shuaikang 2; Yu, Dandan 2
刊名	INTERNATIONAL JOURNAL OF ONCOLOGY
	2018-08
卷号	53 期号:2 页码:823-834
关键词	mantle cell lymphoma dihydrocelastrol apoptosis cell cycle mTORC1 mTORC2
ISSN号	1019-6439
DOI	10.3892/ijo.2018.4438
文献子类	Article
英文摘要	Mantle cell lymphoma (MCL) is a distinct and highly aggressive subtype of B-cell non-Hodgkin lymphoma. Dihydrocelastrol (DHCE) is a dihydro-analog of celastrol, which is isolated from the traditional Chinese medicinal plant Tripterygium wilfordii. The present study aimed to investigate the effects of DHCE treatment on MCL cells, and to determine the mechanism underlying its potent antitumor activity in vitro and in vivo using the Cell Counting kit-8 assay, clonogenic assay, apoptosis assay, cell cycle analysis, immunofluorescence staining, western blotting and tumor xenograft models. The results demonstrated that DHCE treatment exerted minimal cytotoxic effects on normal cells, but markedly suppressed MCL cell proliferation by inducing G(0)/G(1) phase cell cycle arrest, and inhibited MCL cell viability by stimulating apoptosis via extrinsic and intrinsic pathways. In addition, the results revealed that DHCE suppressed cell growth and proliferation by inhibiting mammalian target of rapamycin complex (mTORC)1-mediated phosphorylation of ribosomal protein S6 kinase and eukaryotic initiation factor 4E binding protein. Simultaneously, DHCE induced apoptosis and inhibited cell survival by suppressing mTORC2-mediated phosphorylation of protein kinase B and nuclear factor-B activity. In addition to in vitro findings, DHCE treatment reduced the MCL tumor burden in a xenograft mouse model, without indications of toxicity. Furthermore, combined treatment with DHCE and bortezomib, a proteasome inhibitor, induced a synergistic cytotoxic effect on MCL cells. These findings indicated that DHCE may have the potential to serve as a novel therapeutic agent for the treatment of MCL through dually inhibiting mTORC1 and mTORC2.
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[81602515]
WOS关键词	NF-KAPPA-B ; SINGLE-AGENT TEMSIROLIMUS ; CANCER DEVELOPMENT ; PATHWAY ; ACTIVATION ; APOPTOSIS ; PROGRESSION ; CELASTROL ; MALIGNANCIES ; THERAPY
WOS研究方向	Oncology
语种	英语
出版者	SPANDIDOS PUBL LTD
WOS记录号	WOS:000440581500032
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279646]
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, Dept Hematol, Shanghai 200092, Peoples R China
推荐引用方式 GB/T 7714	Xie, Yongsheng,Li, Bo,Bu, Wenxuan,et al. Dihydrocelastrol exerts potent antitumor activity in mantle cell lymphoma cells via dual inhibition of mTORC1 and mTORC2[J]. INTERNATIONAL JOURNAL OF ONCOLOGY,2018,53(2):823-834.
APA	Xie, Yongsheng.,Li, Bo.,Bu, Wenxuan.,Gao, Lu.,Zhang, Yong.,...&Shi, Jumei.(2018).Dihydrocelastrol exerts potent antitumor activity in mantle cell lymphoma cells via dual inhibition of mTORC1 and mTORC2.INTERNATIONAL JOURNAL OF ONCOLOGY,53(2),823-834.
MLA	Xie, Yongsheng,et al."Dihydrocelastrol exerts potent antitumor activity in mantle cell lymphoma cells via dual inhibition of mTORC1 and mTORC2".INTERNATIONAL JOURNAL OF ONCOLOGY 53.2(2018):823-834.