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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/02/05 04:09:06」(JST)

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Cyclopamine (11-deoxojervine) is a naturally occurring chemical that belongs to the group of steroidal jerveratrum alkaloids. 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.^[1]

Physiological effects

Head of a lamb born by a sheep that ate leaves of the corn lily plant. The cyclopia in the calf is induced by the cyclopamine present in the plant.

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

Medical potential

Cyclopamine is currently being investigated as a treatment agent in basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma, tumors that result from excessive Hh activity,^[2] glioblastoma, and as a treatment agent for multiple myeloma.

Studies suggest that cyclopamine acts as a primary inhibitor of the hedgehog signaling 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.^[3]

The cyclopamine derivative IPI-926 is in clinical trials for the treatment of various types of cancer.^[4]

References

^ Herper, Matthew (2005-11-28). "The Curious Case of The One-Eyed Sheep". Forbes.
^ Beachy, Philip A.; Taipale, Jussi; Chen, James K.; Cooper, Michael K.; Wang, Baolin; Mann, Randall K.; Milenkovic, Ljiljana; Scott, Matthew P. (2000-08-31). "Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine". Nature 406 (6799): 1005–9. doi:10.1038/35023008. PMID 10984056.
^ David Bradley (2009-08-15). "Keeping an eye on anticancer drug". NMR Knowledge Base.
^ "Pipeline: IPI-926". Infinity Pharmaceuticals.

External links

Cancer Drug Behind Cyclops Birth?, Wired News
Experimental Anti-cancer Drug Kills Brain Tumor Stem Cells, Science Daily
Tabs, S; Avci, O (2004). "Induction of the differentiation and apoptosis of tumor cells in vivo with efficiency and selectivity". European Journal of Dermatology 14 (2): 96–102. PMID 15196999.
Taş, S; Avci, O (2004). "Rapid clearance of psoriatic skin lesions induced by topical cyclopamine. A preliminary proof of concept study". Dermatology (Basel, Switzerland) 209 (2): 126–31. doi:10.1159/000079596. PMID 15316166.
Zhang, J; Garrossian, M; Gardner, D; Garrossian, A; Chang, YT; Kim, YK; Chang, CW (2008). "Synthesis and anticancer activity studies of cyclopamine derivatives". Bioorganic & Medicinal Chemistry Letters 18 (4): 1359–63. doi:10.1016/j.bmcl.2008.01.017. PMID 18221872.
Fan, Q; Gu, D; He, M; Liu, H; Sheng, T; Xie, G; Li, C. X.; Zhang, X; Wainwright, B; Garrossian, A; Garrossian, M; Gardner, D; Xie, J (2011). "Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling". Chinese Journal of Cancer 30 (7): 472–81. doi:10.5732/cjc.011.10157. PMC 4013422. PMID 21718593.

English Journal

Oxy133, a novel osteogenic agent, promotes bone regeneration in an intramembranous bone-healing model.

Li A1, Hokugo A1, Segovia LA1, Yalom A1, Rezzadeh K1, Zhou S1, Zhang Z1, Parhami F2, Stappenbeck F3, Jarrahy R1.
Journal of tissue engineering and regenerative medicine.J Tissue Eng Regen Med.2015 Jun 15. doi: 10.1002/term.2047. [Epub ahead of print]
Current reconstructive techniques for complex craniofacial osseous defects are challenging and are associated with significant morbidity. Oxysterols are naturally occurring cholesterol oxidation products with osteogenic potential. In this study, we investigated the effects of a novel semi-synthetic
PMID 26073881

Biochemical characterization of smoothened receptor antagonists by binding kinetics against drug-resistant mutant.

Shimizu Y1, Ishii T2, Ogawa K2, Sasaki S2, Matsui H2, Nakayama M2.
European journal of pharmacology.Eur J Pharmacol.2015 Jun 2. pii: S0014-2999(15)30062-5. doi: 10.1016/j.ejphar.2015.05.062. [Epub ahead of print]
Hedgehog (Hh) signaling critical for development, differentiation, and cell growth is involved in several cancers, including medulloblastoma and basal cell carcinoma. Although antagonism of the smoothened receptor (SMO), which mediates Hh signaling, is an attractive therapeutic target, a drug-resist
PMID 26048307

Hedgehog signaling is involved in the BMP9-induced osteogenic differentiation of mesenchymal stem cells.

Li L1, Dong Q1, Wang Y1, Feng Q1, Zhou P2, Ou X1, Meng Q1, He T1, Luo J1.
International journal of molecular medicine.Int J Mol Med.2015 Jun;35(6):1641-50. doi: 10.3892/ijmm.2015.2172. Epub 2015 Apr 7.
Nonunion is a serious complication of a bone fracture that may occur in any bone of the skeletal system. It occurs when a broken bone fails to heal. Mesenchymal stem cell (MSC)-based tissue engineering technology has been considered an efficient method to improve the healing rate of nonunions. Altho
PMID 25872645

Japanese Journal

Smoothened as a new therapeutic target for human osteosarcoma

HIROTSU Masataka,SETOGUCHI Takao,MATSUNOSHITA Yukihiro,GAO Hui,NAGAO Hiroko,KUNIGOU Osamu,KOMIYA Setsuro,ヒロツマサタカ,セトグチタカオ,マツノシタユキヒロ,ナガオヒロコ,クニゴウオサム,コミヤセツロウ,廣津匡隆,瀬戸口啓夫,松野下幸弘,永尾宗子,救仁郷修,小宮節郎
Molecular Cancer 9(5), 2012-01-12
… Inhibition of SMO by cyclopamine, a specific inhibitor of SMO, slowed the growth of osteosarcoma in vitro. … Cell cycle analysis revealed that cyclopamine promoted G1 arrest. … Cyclopamine reduced the expression of accelerators of the cell cycle including cyclin D1, cyclin E1, SKP2, and pRb. … On the other hand, p21cip1 wprotein was up-regulated by cyclopamine treatment. …
NAID 120005342572

Pharmacological inhibition of the Hedgehog pathway prevents human rhabdomyosarcoma cell growth

KAWABATA Naoya,IJIRI Kosei,ISHIDOU Yasuhiro,YAMAMOTO Takuya,NAGAO Hiroko,NAGANO Satoshi,MAEDA Shingo,KOMIYA Setsuro,SETOGUCHI Takao,カワバタナオヤ,イジリコウセイ,イシドウヤスヒロ,ヤマモトタクヤ,ナガオヒロコ,ナガノサトシ,マエダシンゴ,コミヤセツロウ,セトグチタカオ,川畑直也,井尻幸成,石堂康弘,山元拓哉,永尾宗子,永野聡,前田真吾,小宮節郎,瀬戸口啓夫
International Journal of Oncology 39(4), 899-906, 2011-06-14
… Further, we evaluated the effect of pharmacological inhibition of the Hedgehog pathway using cyclopamine or GANT61 by WST assay, cell proliferation assay and cell death detection assay. … Inhibition of SMO by cyclopamine slowed the growth of human rhabdomyosarcoma cell lines. … Inhibition of cell proliferation and apoptotic cell death together prevented the growth of rhabdomyosarcoma cells by cyclopamine and GANT61 treatment. …
NAID 120005342568

Hedgehog Promotes Neovascularization in Pancreatic Cancers by Regulating Ang-1 and IGF-1 Expression in Bone-Marrow Derived Pro-Angiogenic Cells

中村和正,Sasajima Junpei,Mizukami Yusuke,Sugiyama Yoshiaki,Yamazaki Madoka,Fujii Rie,Kawamoto Toru,Koizumi Kazuya,Sato Kazuya,Fujiya Mikihiro,Sasaki Katsunori,Tanno Satoshi,Okumura Toshikatsu,Shimizu Norihiko,Kawabe Junichi,Karasaki Hidenori,Kono Toru,Ii Masaaki,Bardeesy Nabeel,Chung Daniel C.,Kohgo Yutaka
PloS one 5(1), e8824-1-e8824-11, 2010-01
… Methodology/Principal Findings: Cyclopamine was utilized to inhibit the Hh pathway in human PDAC cell lines and their xenografts. … Cyclopamine administration attenuated Hh signaling in the stroma rather than in the cancer cells as reflected by decreased expression of full length Gli2 protein and Gli1 mRNA specifically in the compartment. … Cyclopamine inhibited the growth of PDAC xenografts in association with regression of the tumor vasculature and reduced homing of BM-derived cells to the tumor. …
NAID 120004138817

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リンク元	「シクロパミン」「サイクロパミン」

「シクロパミン」

Cyclopamine
	IUPAC name (3β,23R)-17,23-Epoxyveratraman-3-ol
	Other names • 11-Deoxojervine; • (2′R,3S,3′R,3′aS,6′S,6aS,6bS,7′aR,11aS,11bR)-1,2,3,3′a,4,4′,5′,6,6′,6a,6b,7,7′,7'a,8,11,11a,11b-octadecahydro-3′,6′,10,11b-tetramethyl-spiro[9H-benzo[a]fluorene-9,2′(3′H)-furo[3,2-b]pyridin]-3-ol
Identifiers
CAS number	4449-51-8
PubChem	442972
ChemSpider	391275
UNII	ZH658AJ192
ChEMBL	CHEMBL254129
Jmol-3D images	Image 1
	SMILES C[C@H]1C[C@@H]2[C@H]([C@H]([C@]3(O2)CC[C@H]4[C@@H]5CC=C6C[C@H](CC[C@@]6([C@H]5CC4=C3C)C)O)C)NC1 ;
	InChI InChI=1S/C27H41NO2/c1-15-11-24-25(28-14-15)17(3)27(30-24)10-8-20-21-6-5-18-12-19(29)7-9-26(18,4)23(21)13-22(20)16(27)2/h5,15,17,19-21,23-25,28-29H,6-14H2,1-4H3/t15-,17+,19-,20-,21-,23-,24+,25-,26-,27-/m0/s1 ; Key: QASFUMOKHFSJGL-LAFRSMQTSA-N InChI=1/C27H41NO2/c1-15-11-24-25(28-14-15)17(3)27(30-24)10-8-20-21-6-5-18-12-19(29)7-9-26(18,4)23(21)13-22(20)16(27)2/h5,15,17,19-21,23-25,28-29H,6-14H2,1-4H3/t15-,17+,19-,20-,21-,23-,24+,25-,26-,27-/m0/s1; Key: QASFUMOKHFSJGL-LAFRSMQTBZ ;
Properties
Molecular formula	C27H41NO2
Molar mass	411.62 g mol−1
	Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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	Infobox references

　　[★]

英: cyclopamine
関: サイクロパミン

「サイクロパミン」

　　[★]

英: cyclopamine
関: シクロパミン

[1] Herper, Matthew (2005-11-28). "The Curious Case of The One-Eyed Sheep". Forbes.

[2] Beachy, Philip A.; Taipale, Jussi; Chen, James K.; Cooper, Michael K.; Wang, Baolin; Mann, Randall K.; Milenkovic, Ljiljana; Scott, Matthew P. (2000-08-31). "Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine". Nature 406 (6799): 1005–9. doi:10.1038/35023008. PMID 10984056.

[3] David Bradley (2009-08-15). "Keeping an eye on anticancer drug". NMR Knowledge Base.

[4] "Pipeline: IPI-926". Infinity Pharmaceuticals.

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cyclopamine