New tanshinone I derivatives S222 and S439 similarly inhibit topoisomerase I/II but reveal different p53-dependency in inducing G2/M arrest and apoptosis

doi:10.1016/j.bcp.2018.05.006

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	New tanshinone I derivatives S222 and S439 similarly inhibit topoisomerase I/II but reveal different p53-dependency in inducing G2/M arrest and apoptosis
	Tian, Qian-Ting 1,2; Ding, Chun-Yong3 ; Song, Shan-Shan 2; Wang, Ying-Qing2 ; Zhang, Ao3 ; Miao, Ze-Hong 2
刊名	BIOCHEMICAL PHARMACOLOGY
	2018-08
卷号	154 页码:255-264
关键词	Tanshinone-1 S222 S439 Anticancer targets DNA topoisomerases P53
ISSN号	0006-2952
DOI	10.1016/j.bcp.2018.05.006
文献子类	Article
英文摘要	Tanshinone I (Tanshinone-1), a major active principle of the traditional Chinese medicine Salvia miltiorrhiza, possesses excellent anticancer properties, including inhibiting proliferation, angiogenesis and metastasis and overcoming multidrug resistance (MDR). However, its direct anticancer molecular target(s) remain unknown. Here we report that tanshinone-1 and its two new derivatives, S222 and S439, directly inhibit DNA topoisomerase I/II (Top1/2). With significantly improved water solubility, S222 and S439 displayed 12- and 14-times more potent proliferative inhibition than their parent tanshinone-1 in a panel of 15 cancer cell lines. Both retained tanshinone-1's anti-MDR and anti-angiogenesis properties and its capability to reduce the phosphorylation of Stat3 at Tyr705 with apparently enhanced efficacy and in these regards, S439 was also slightly more potent than S222. Both derivatives and tanshinone-1 directly inhibited Top1 and Top2 at molecular and cellular levels; the derivatives displayed similar potency but both were more potent than tanshinone-1. The inhibition of S222 and S439 on Top1 and Top2 was also more potent than that of the Top1 inhibitor hydroxylcamptothecin and the Top2 inhibitor etoposide, respectively. Consistently, tanshinone-1 and its derivatives induced DNA double-strand breaks, G2/M arrest and apoptosis Unexpectedly, the derivatives demonstrated different p53-dependency in inducing both cell cycle arrest and apoptosis. S222 showed no obvious p53 dependency. In contrast, S439 induced more G2/M arrest in p53 proficient cells than in p53 deficient cells while its apoptotic induction was the opposite. However, their proliferative inhibition was independent of the p53 status. Due to their structures different from the known Top1, Top2 and dual Top1/2 inhibitors, our results indicate that tanshinone-1 and its derivatives are a new type of dual Top1/2 inhibitors.
资助项目	Chinese Academy of Sciences[XDA12020331]
WOS关键词	TUMOR-CELLS ; SALVICINE ; BIOMARKER ; CLEAVAGE ; PATHWAY ; GROWTH ; CYCLE ; VIVO
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000441369600026
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279641]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物化学研究室
通讯作者	Wang, Ying-Qing; Zhang, Ao; Miao, Ze-Hong
作者单位	1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Dept Med Chem, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Tian, Qian-Ting,Ding, Chun-Yong,Song, Shan-Shan,et al. New tanshinone I derivatives S222 and S439 similarly inhibit topoisomerase I/II but reveal different p53-dependency in inducing G2/M arrest and apoptosis[J]. BIOCHEMICAL PHARMACOLOGY,2018,154:255-264.
APA	Tian, Qian-Ting,Ding, Chun-Yong,Song, Shan-Shan,Wang, Ying-Qing,Zhang, Ao,&Miao, Ze-Hong.(2018).New tanshinone I derivatives S222 and S439 similarly inhibit topoisomerase I/II but reveal different p53-dependency in inducing G2/M arrest and apoptosis.BIOCHEMICAL PHARMACOLOGY,154,255-264.
MLA	Tian, Qian-Ting,et al."New tanshinone I derivatives S222 and S439 similarly inhibit topoisomerase I/II but reveal different p53-dependency in inducing G2/M arrest and apoptosis".BIOCHEMICAL PHARMACOLOGY 154(2018):255-264.