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Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis
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AT-101 inhibits hedgehog pathway activity and cancer growth

Juan Wang1, Yuanqiu Peng, Yuan Liu

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

Cancer Chemotherapy and Pharmacology
|June 27, 2015
PubMed
Abstract

Insights

AT-101, a Bcl-2 inhibitor, effectively blocks the hedgehog (Hh) signaling pathway by targeting Smo. This action suppresses Hh-driven cancers, revealing a novel anticancer mechanism for AT-101 development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • AT-101 is a BH3 mimetic investigated as a pan-inhibitor of anti-apoptotic Bcl-2 family proteins.
  • The hedgehog (Hh) signaling pathway is implicated in various cancers, making it a therapeutic target.

Purpose of the Study:

  • To evaluate the effect of AT-101 on Hh signaling pathway activity.
  • To assess the anticancer ability of AT-101 in Hh-driven cancers.

Main Methods:

  • In vitro and in vivo assays were employed.
  • The study utilized a patch+/-; p53-/- mouse medulloblastoma model.
  • Binding site analysis with cyclopamine was performed to understand AT-101's mechanism.

Main Results:

  • AT-101 demonstrated significant inhibition of Hh signaling pathway activity.
  • The inhibition showed selectivity towards the Hh pathway.
  • AT-101 was found to potentially target Smo, sharing a binding site with cyclopamine.
  • AT-101 suppressed Hh-driven medulloblastoma growth both in vitro and in vivo.

Conclusions:

  • AT-101 selectively inhibits the Hh pathway by targeting Smo.
  • This inhibition leads to the suppression of Hh-driven cancer growth.
  • The study reveals a novel mechanism for AT-101's anticancer action, supporting its development.

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