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Cancer Chemotherapy and Pharmacology

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01.09.2015 | Original Article

AT-101 inhibits hedgehog pathway activity and cancer growth

verfasst von: Juan Wang, Yuanqiu Peng, Yuan Liu, Jun Yang, Ming Huang, Wenfu Tan

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 3/2015

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Abstract

Purpose

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.

Results

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.

Conclusions

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.

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Titel: AT-101 inhibits hedgehog pathway activity and cancer growth
verfasst von: Juan Wang
Yuanqiu Peng
Yuan Liu
Jun Yang
Ming Huang
Wenfu Tan
Publikationsdatum: 01.09.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 3/2015
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2812-x

Springer Medizin

AT-101 inhibits hedgehog pathway activity and cancer growth

Abstract

Purpose

Results

Conclusions

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Update Onkologie

Springer Medizin

Abstract

Purpose

Results

Conclusions

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