CyclopamineS1146

Cyclopamine inhibits the Hedgehog signaling pathway with an IC50 of 46 nM, and blocks the activity of human Smo receptor expressed in CHO-K1 cells in [³H]Hh-Ag binding assay with an IC50 of 280 nM. ^[1] Cyclopamine significantly inhibits Hedgehog pathway activity in a dose-dependent manner in gut-derived tumor cell lines expressing Patched (PTCH) mRNA, and induces growth inhibition of those tumor cell lines by 75-95% at the concentration of 3 μM, but ineffective towards the colon tumor cells without PTCH mRNA expression, suggesting the effects of Cyclopamine treatment are Hedgehog pathway related rather than generally cytotoxic. ^[2] By blocking Hedgehog signaling through direct interaction with Smo, Cyclopamine (10 μM) inhibits the proliferation of SMO^high Cyclopamine-responsive cell lines L3.6sl and Panc 05.04 by 75-80%, and increases the apoptosis by 2.5- to 3.5-fold, without affecting the BxPC3-SMO^low cell line. ^[3] Cyclopamine treatment significantly decreases of Snail mRNA and increasea E-cadherin transcripts in the E3LZ10.7 cell line. Independent of inhibition of cell growth, Cyclopamine treatment significantly inhibits the invasive phenotype of Hedgehog-dependent L3.6pl cells, causing a >500-fold reduction in the number of transmigrating cells, but not that of the Hedgehog-independent cell line Panc-1. ^[4]