Home > A. Molecular pathology > Metabolome > cyclopamine

cyclopamine

Thursday 20 December 2012

WKP

Cyclopamine (11-deoxojervine) is a naturally occurring chemical that belongs to the group of steroidal jerveratrum alkaloids.

SHH pathway inhibition

Cyclopamine inhibits the hedgehog signaling pathway (Hh) by influencing the balance between the active and inactive forms of the smoothened protein.

Cyclopamine can prevent the fetal brain from dividing into two lobes (holoprosencephaly) and cause the development of a single eye (cyclopia). It does so by inhibiting the hedgehog signaling pathway (Hh).

Cyclopamine is useful in studying the role of Hh in normal development, and as a potential treatment for certain cancers in which Hh is overexpressed.

Teratogenesis

Cyclopamine is a teratogen isolated from the corn lily (Veratrum californicum) that causes usually fatal birth defects.

Cyclopamine was named for one-eyed lambs which were born to sheep which grazed on wild corn lily at a farm in Idaho.

In 1957 the US Department of Agriculture started an eleven-year investigation which led to the identification of cyclopamine as the cause of the birth defect.

Therapeutics

Cyclopamine is currently being investigated as a treatment agent in basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma, tumors that result from excessive Hh activity, glioblastoma, and as a treatment agent for multiple myeloma.

Studies suggest that cyclopamine acts as a primary inhibitor of the so-called "hedgehog" signal-transduction pathway in cells (SHH pathway).

The SHH pathway, named for the ligand for the signal protein, is used by cells to help them react to external chemical signals.

The SHH pathway carries out important functions in embryonic development and when it goes awry, deformities can occur.

However, errant activation of the pathway can also trigger cancer in adult humans, leading to basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and prostate, pancreatic and breast cancers.

A way of controlling the pathway using cyclopamine could turn this problem on its head and provide a way to treat cancer.

Many anticancer drugs are paradoxically carcinogenic in healthy individuals.

The cyclopamine derivative saridegib (IPI-926) is in clinical trials for the treatment of various types of cancer.

Artificial Hh signaling inhibitors

- saridegib (IPI-926=)
- vismodegib
- erismodegib