A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe

doi:10.1186/s13046-020-01597-9

	A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe
	Hu,Liangning 1; Li,Bo 2; Chen,Gege 1; Song,Dongliang 1; Xu,Zhijian 2; Gao,Lu 1; Xi,Mengyu 2; Zhou,Jinfeng 1; Li,Liping 1; Zhang,Hui 1
刊名	Journal of Experimental & Clinical Cancer Research
	2020-06-09
卷号	39 期号:1
关键词	Multiple myeloma Drug-resistance DNA damage response Cell cycle
DOI	10.1186/s13046-020-01597-9
通讯作者	Zhu,Weiliang(wlzhu@simm.ac.cn) ; Shi,Jumei(shijumei@tongji.edu.cn)
英文摘要	AbstractBackgroundDCZ3301, a novel aryl-guanidino compound previously reported by our group, exerts cytotoxic effects against multiple myeloma (MM), diffused large B cell lymphoma (DLBCL), and T-cell leukemia/lymphoma. However, the underlying mechanism of its action remains unknown.MethodsWe generated bortezomib (BTZ)-resistant cell lines, treated them with various concentrations of DCZ3301 over varying periods, and studied its effect on colony formation, cell proliferation, apoptosis, cell cycle, DNA synthesis, and DNA damage response. We validated our results using in vitro and in vivo experimental models.ResultsDCZ3301 overcame bortezomib (BTZ) resistance through regulation of the G2/M checkpoint in multiple myeloma (MM) in vitro and in vivo. Furthermore, treatment of BTZ-resistant cells with DCZ3301 restored their drug sensitivity. DCZ3301 induced M phase cell cycle arrest in MM mainly via inhibiting DNA repair and enhancing DNA damage. Moreover, DCZ3301 promoted the phosphorylation of ATM, ATR, and their downstream proteins, and these responses were blocked by the ATM specific inhibitor KU55933.ConclusionsOur study provides a proof-of-concept that warrants the clinical evaluation of DCZ3301 as a novel anti-tumor compound against BTZ resistance in MM.
语种	英语
出版者	BioMed Central
WOS记录号	BMC:10.1186/S13046-020-01597-9
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280143]
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.Shanghai Tenth People’s Hospital, Tongji University School of Medicine; Department of Hematology 2.Shanghai Institute of Materia Medica, Chinese Academy of Sciences; CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center 3.Tongji University Cancer Center, Tongji University
推荐引用方式 GB/T 7714	Hu,Liangning,Li,Bo,Chen,Gege,et al. A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe[J]. Journal of Experimental & Clinical Cancer Research,2020,39(1).
APA	Hu,Liangning.,Li,Bo.,Chen,Gege.,Song,Dongliang.,Xu,Zhijian.,...&Shi,Jumei.(2020).A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe.Journal of Experimental & Clinical Cancer Research,39(1).
MLA	Hu,Liangning,et al."A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe".Journal of Experimental & Clinical Cancer Research 39.1(2020).