Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade

Abstract

antagonist ͉ cancer ͉ Gli ͉ medulloblastoma

Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2

“…We therefore determined whether these processes are affected by inactivation of Evc/Evc2. We made use of cell lines that stably express Flag-tagged Gli2 (Shh-EGFP FLAG-Gli2 ) or Gli1 (Shh-LIGHT2 FLAG-Gli1 ) [38]. Consistent with a previous study [38], Shh induced accumulation of Flag-Gli1 and Flag-Gli2 at the tip of primary cilia, which is indicative of Gli activation (Figure 5B, 5H and Supplementary information, Figure S3).…”

“…We made use of cell lines that stably express Flag-tagged Gli2 (Shh-EGFP FLAG-Gli2 ) or Gli1 (Shh-LIGHT2 FLAG-Gli1 ) [38]. Consistent with a previous study [38], Shh induced accumulation of Flag-Gli1 and Flag-Gli2 at the tip of primary cilia, which is indicative of Gli activation (Figure 5B, 5H and Supplementary information, Figure S3). When cells are infected with high-titer Evc/Evc2 shRNA expression viruses, the accumulation of Flag-Gli1 and Flag-Gli2 at the tip of primary cilia was significantly reduced ( Figure 5C-5F, 5I-5L and Supplementary information, Figure S3), suggesting that Gli activation is attenuated by inactivation of Evc/Evc2.…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Robotnikinin inhibits Shh signaling in a concentrationdependent manner but shows no inhibitory activity in a cell line lacking the Ptc1 receptor, does not compete with cyclopamine-Smo interactions and does not show an inhibitory effect in the presence of the well- (Stanton et al, 2009). A few small-molecule inhibitors for Gli1 functions are identified through chemical library screening (Lauth et al, 2007;Hyman et al, 2009). Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway (Lauth et al, 2007).…”

Targeting the CB2 cannabinoid receptor in osteoporosis

“…Robotnikinin, a drug that blocks the interaction of Shh with receptors [90], is of this class. Further down the pathway, the knowledge that Gli activity may be an important factor in tumor biology, independent of hedgehog signaling, has also driven discovery efforts to identify drugs that can block this activity, and the Gli antagonists (GANTs; -58 and -61) [91], and, more recently, the HPI class of drugs [92] that interfere with Gli trafficking and transcription, may have clinical applicability. Finally, the actions of arsenic trioxide, which is being tested as a solid tumor therapeutic [93], may also include the inactivation of Gli function in cancer cells [94,95] so this drug may provide an alternative option for hedgehog targeting in cancers.…”