AT-101 inhibits hedgehog pathway activity and cancer growth.

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.