Journal
CANCER CHEMOTHERAPY AND PHARMACOLOGY
Volume 76, Issue 3, Pages 461-469Publisher
SPRINGER
DOI: 10.1007/s00280-015-2812-x
Keywords
Hedgehog; AT-101; Gossypol; Medulloblastoma; Smoothened
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Funding
- Shanghai Municipal Science & Technology Pillar Program for Bio-pharmaceuticals [14431900400]
- State Key Laboratory of Drug Research [SIMM1501KF-09]
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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.
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