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Cancer Lett. 2018 Apr 28;420:195-207. doi: 10.1016/j.canlet.2018.02.005. Epub 2018 Feb 6.

Cynanbungeigenin C and D, a pair of novel epimers from Cynanchum bungei, suppress hedgehog pathway-dependent medulloblastoma by blocking signaling at the level of Gli.

Author information

1
Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou, 310013, China.
2
Zhejiang Cancer Hospital, Hangzhou, 310022, China.
3
Department of Basic Medical Science, Hangzhou Medical College, Hangzhou, 310053, China. Electronic address: Chenfy_hz@126.com.
4
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China.
5
Institute of Materia Medica, Zhejiang Academy of Medical Sciences, Hangzhou, 310013, China. Electronic address: yeyiping2005@zjams.com.cn.

Abstract

Uncontrolled excessive activation of Hedgehog (Hh) signaling pathway is linked to a number of human malignant tumorigenesis. To obtain valuable Hh pathway inhibitors from natural product, in present study, a pair of novel epimers, Cynanbungeigenin C (CBC) and D (CBD) from the plant Cynanchum bungei Decne were chemically characterized by multiple spectroscopic data and chemical derivatization, and evaluated for their inhibition on Hh pathway. Mechanistically, CBC and CBD block Hh pathway signaling not through targeting Smo and Sufu, but at the level of Gli. In addition, both eipmers significantly suppress Hh pathway-dependent Ptch+/-; p53-/- medulloblastoma in vitro and in vivo. Furthermore, both CBC and CBD inhibited two Smo mutants induced Hh pathway activation, which suggested that they are potential compounds for the treatment of medulloblastoma with primary or acquired resistance to current Smo inhibitors. These results highlight the potential of CBC and CBD as effective lead compounds in the treatment of medulloblastoma and other Hh-dependent malignancy.

KEYWORDS:

Acquired resistance; C(21) steroid; Gli inhibitor; Hh pathway inhibitor; Medulloblastoma; Natural product

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