title: AT-101 inhibits hedgehog pathway activity and cancer growth.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.forename: Yuanqiu
authors.initials: Y
authors.lastname: Peng
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Ming
authors.initials: M
authors.lastname: Huang
authors.forename: Wenfu
authors.initials: W
authors.lastname: Tan
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053823:Hedgehog Proteins; D006072:Gossypol; C028178:gossypol acetic acid