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AT-101 inhibits hedgehog pathway activity and cancer growth

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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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Acknowledgments

This study was financially supported by Shanghai Municipal Science & Technology Pillar Program for Bio-pharmaceuticals (14431900400) and the State Key Laboratory of Drug Research (SIMM1501KF-09).

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    Authors and Affiliations

    1. Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People’s Republic of China

      Juan Wang, Yuanqiu Peng, Yuan Liu, Jun Yang & Wenfu Tan

    2. Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China

      Ming Huang & Wenfu Tan

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    1. Juan Wang
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    Correspondence to Wenfu Tan.

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    Juan Wang and Yuanqiu Peng have contributed equally to this study.

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    Wang, J., Peng, Y., Liu, Y. et al. AT-101 inhibits hedgehog pathway activity and cancer growth. Cancer Chemother Pharmacol 76, 461–469 (2015). https://doi.org/10.1007/s00280-015-2812-x

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