Cyclopamine
Encyclopedia
Cyclopamine is a naturally occurring chemical that belongs to the group of steroidal jerveratrum alkaloid
s. It is a teratogen isolated from the corn lily (Veratrum californicum
) that causes usually fatal birth defects. It 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.
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.
(Hh) by influencing the balance between the active and inactive forms of the smoothened
protein.
, 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. This pathway named for the ligand for the signal protein, is used by cells to help them react to external chemical signals. The 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
IPI-926
is in clinical trials for the treatment of various types of cancer.
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
s. It is a teratogen isolated from the corn lily (Veratrum californicum
Veratrum californicum
Veratrum californicum is a poisonous plant native to mountain meadows at 3500 to 11,000ft elevation in southwestern North America, the Sierra Nevada and Rocky Mountains, and as far north as Washington State. It grows 1 to 2 meters tall, with an erect, unbranched, heavily leafy stem resembling a...
) that causes usually fatal birth defects. It can prevent the fetal brain from dividing into two lobes (holoprosencephaly
Holoprosencephaly
Holoprosencephaly is a cephalic disorder in which the prosencephalon fails to develop into two hemispheres. Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of human pregnancy...
) and cause the development of a single eye (cyclopia
Cyclopia
Cyclopia is a rare form of holoprosencephaly and is a congenital disorder characterized by the failure of the embryonic prosencephalon to properly divide the orbits of the eye into two cavities...
). It does so by inhibiting the hedgehog signaling pathway
Hedgehog signaling pathway
In a growing embryo, cells develop differently in the head or tail end of the embryo, the left or right, and other positions. They also form segments which develop into different body parts. The hedgehog signaling pathway gives cells information that they need to make the embryo develop properly....
(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.
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.
Physiological effects
Cyclopamine inhibits the hedgehog signaling pathwayHedgehog signaling pathway
In a growing embryo, cells develop differently in the head or tail end of the embryo, the left or right, and other positions. They also form segments which develop into different body parts. The hedgehog signaling pathway gives cells information that they need to make the embryo develop properly....
(Hh) by influencing the balance between the active and inactive forms of the smoothened
Smoothened
Smoothened is a G protein-coupled receptor protein encoded by the gene of the hedgehog pathway conserved from flies to humans. It is the molecular target of the teratogen cyclopamine....
protein.
Medical potential
Cyclopamine is currently being investigated as a treatment agent in basal cell carcinomaBasal cell carcinoma
Basal-cell carcinoma is the most common type of skin cancer. It rarely metastasizes or kills. However, because it can cause significant destruction and disfigurement by invading surrounding tissues, it is still considered malignant. Statistically, approximately 3 out of 10 Caucasians may develop a...
, medulloblastoma
Medulloblastoma
Medulloblastoma is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa.Previously, medulloblastomas were thought to represent a subset of primitive neuroectodermal tumor of the posterior fossa...
, and rhabdomyosarcoma
Rhabdomyosarcoma
A rhabdomyosarcoma is a type of cancer, specifically a sarcoma , in which the cancer cells are thought to arise from skeletal muscle progenitors. It can also be found attached to muscle tissue, wrapped around intestines, or in any anatomic location...
, tumors that result from excessive Hh activity, glioblastoma, and as a treatment agent for multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
.
Studies suggest that cyclopamine acts as a primary inhibitor of the so-called "hedgehog" signal-transduction pathway in cells. This pathway named for the ligand for the signal protein, is used by cells to help them react to external chemical signals. The 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
Derivative (chemistry)
In chemistry, a derivative is a compound that is derived from a similar compound by some chemical or physical process. In the past it was also used to mean a compound that can be imagined to arise from another compound, if one atom is replaced with another atom or group of atoms, but modern...
IPI-926
IPI-926
IPI-926 is an experimental drug candidate currently undergoing clinical trials for the treatment of various types of cancer. IPI-926 exhibits its pharmacological effect by inhibition of the G protein-coupled receptor smoothened, a component of the hedgehog signaling pathway. Chemically, it is a...
is in clinical trials for the treatment of various types of cancer.
External links
- Cancer Drug Behind Cyclops Birth?, Wired News
- Experimental Anti-cancer Drug Kills Brain Tumor Stem Cells, Science Daily