AT-101 inhibits hedgehog pathway activity and cancer growth

doi:10.1007/s00280-015-2812-x

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	AT-101 inhibits hedgehog pathway activity and cancer growth
	Wang, Juan 1; Peng, Yuanqiu 1; Liu, Yuan 1; Yang, Jun 1; Huang, Ming 2; Tan, Wenfu 1,2
刊名	CANCER CHEMOTHERAPY AND PHARMACOLOGY
	2015-09
卷号	76 期号:3 页码:461-469
关键词	Hedgehog AT-101 Gossypol Medulloblastoma Smoothened
ISSN号	0344-5704
DOI	10.1007/s00280-015-2812-x
文献子类	Article
英文摘要	AT-101 is considered as a putative pan-inhibitor of anti-apoptotic Bcl-2 family protein members acting as a BH3 mimetic. It is currently being investigated in phase I/II clinical trial in various types of cancers. In this study, using a series of in vitro and in vivo assays, we evaluated the effect of AT-101 on the hedgehog (Hh) signaling pathway activity and its anticancer ability. We found that AT-101 obviously blocked the Hh signaling pathway activity in response to ShhN-conditioned medium (ShhN CM). This inhibitory effect, to some extent, displayed selectivity against Hh signaling pathway. Furthermore, we identified that AT-101 potentially acted on smoothened (Smo) by sharing the same binding site with cyclopamine, a classical Hh signaling pathway inhibitor. Taking advantage of the patch+/-; p53-/- mouse medulloblastoma model, we observed that AT-101 significantly suppressed the Hh-driven medulloblastoma growth in vitro and in vivo. This study demonstrates that AT-101 significantly and selectively inhibits Hh pathway activity by potentially targeting Smo and consequently suppresses the growth of Hh-driven cancer. Therefore, this study reveals a novel molecular mechanism responsible for the anticancer action of AT-101 and contributes to the further development of AT-101 as an anticancer drug.
资助项目	Shanghai Municipal Science & Technology Pillar Program for Bio-pharmaceuticals[14431900400] ; State Key Laboratory of Drug Research[SIMM1501KF-09]
WOS关键词	CELL LUNG-CANCER ; SMALL-MOLECULE INHIBITOR ; PROSTATE-CANCER ; IN-VIVO ; ENDOPLASMIC-RETICULUM ; PHASE I/II ; GOSSYPOL ; ANTAGONISTS ; PROTEINS ; BCL-2
WOS研究方向	Oncology ; Pharmacology & Pharmacy
语种	英语
出版者	SPRINGER
WOS记录号	WOS:000359817800003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276425]
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
通讯作者	Tan, Wenfu
作者单位	1.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Wang, Juan,Peng, Yuanqiu,Liu, Yuan,et al. AT-101 inhibits hedgehog pathway activity and cancer growth[J]. CANCER CHEMOTHERAPY AND PHARMACOLOGY,2015,76(3):461-469.
APA	Wang, Juan,Peng, Yuanqiu,Liu, Yuan,Yang, Jun,Huang, Ming,&Tan, Wenfu.(2015).AT-101 inhibits hedgehog pathway activity and cancer growth.CANCER CHEMOTHERAPY AND PHARMACOLOGY,76(3),461-469.
MLA	Wang, Juan,et al."AT-101 inhibits hedgehog pathway activity and cancer growth".CANCER CHEMOTHERAPY AND PHARMACOLOGY 76.3(2015):461-469.