AT-101 inhibits hedgehog pathway activity and cancer growth

• DOI: 10.1007/s00280-015-2812-x
• Publication Date: 2015-06-25T08:20:44Z
• Authors: Juan Wang; Yuanqiu Peng; Yuan Liu; Jun Yang; Ming Huang; Wenfu Tan
• Keywords: Mice, Inbred C3H; 0303 health sciences; Gossypol; Mice, Transgenic; Antineoplastic Agents, Phytogenic; 3. Good health; Mice; 03 medical and health sciences; HEK293 Cells; Cell Line, Tumor; Colonic Neoplasms; NIH 3T3 Cells; Animals; Humans; Hedgehog Proteins; Cerebellar Neoplasms; Cell Proliferation; Medulloblastoma; Signal Transduction

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.