Gilding the Lily: Treatment for Basal Cell Carcinoma?

Ingestion of cyclopamine, a plant alkaloid derived from Veratrum californicum , by gravid sheep leads to the deformity of the fetal sheep, while sparing the adult. Cyclopamine inhibits signaling through the sonic hedgehog (Shh) pathway. On the other hand, constitutive activation of Shh (which derepresses Patched inhibition of Smoothened) is found in some human cancers. Taipale et al . now identify that cyclopamine may become a useful chemotherapeutic agent to fight basal cell carcinoma--a type of cancer that often evidences overactive Shh signaling. Patched-deficient mouse embryo fibroblasts transfected with a Shh-sensitive reporter gene exhibited suppressed transcriptional activity in the presence of cyclopamine. However, cyclopamine did not prevent reporter gene transactivation in cells cotransfected with Gli2, a transcriptional activator in the Shh pathway, indicating that cyclopamine's effects probably occur downstream of Patched and upstream of Gli. Expression of Smoothened, in the absence of Shh, led to increased reporter gene expression, which was sensitive to cyclopamine treatment, suggesting that cyclopamine's actions were directed against Smoothened protein. Constitutively activated Smoothened was inhibited by cyclopamine, but only at high doses. Treatment of tumorigenic Patched-deficient cells in vitro with a derivative of cyclopamine inhibited cell growth and colony formation. The authors suggest that cyclopamine affects the ability of Smoothened to be activated in the cell, rendering Smoothened into an inactive conformation. An accompanying News & Views comment by Bale discusses the deformities that are caused by ingestion of the corn lily plant and that arise from improper Hedgehog signaling. Taipale, J., Chen, J.K., Cooper, M.K., Wang, B., Mann, R.K., Milenkovic, L., Scott, M.P., and Beachy, P.A. (2000) Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406 : 1005-1009. [Online Journal] Bale, A.E. (2000) Cancer: Sheep, lilies and human genetics. Nature 406 : 944-945. [Online Journal]