From teratogens to potential therapeutics: Natural inhibitors of the hedgehog signaling network come of age

Planta Medica

Volumn 75, Issue 13, 2009, Pages 1371-1380

  Hovhannisyan, Amalya ^a   Matz, Madlen ^a   Gebhardt, Rolf ^a  

^a UNIVERSITY OF LEIPZIG   (Germany)

Author keywords

Cyclopamine; Hedgehog signaling; Homeostasis; Liliaceae; Psoriasis; Tumor; Veratrum californicum (Durand)

Indexed keywords

CASPASE 3; COLECALCIFEROL; CYCLOPAMINE; CYCLOSPORIN; GERMINE DERIVATIVE; JERVINE; PROTEIN PATCHED 1; SONIC HEDGEHOG PROTEIN; TRANSCRIPTION FACTOR GLI2; UNCLASSIFIED DRUG; VERATRAMINE; VERATROSINE; VERATRUM ALKALOID;

ADIPOGENESIS; ANTINEOPLASTIC ACTIVITY; BASAL CELL NEVUS SYNDROME; BILE DUCT CARCINOMA; BODY WEIGHT; BONE; BREAST CANCER; CANCER INHIBITION; CARCINOGENESIS; CARDIOVASCULAR SYSTEM; CELL PROLIFERATION; CELL TRANSDIFFERENTIATION; CELL VIABILITY; CENTRAL NERVOUS SYSTEM; CONCENTRATION RESPONSE; CYCLOPIA; DOPAMINERGIC SYSTEM; DOWN REGULATION; DRUG BINDING SITE; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG TARGETING; ENZYME ACTIVITY; ESOPHAGUS CARCINOMA; GABAERGIC SYSTEM; GASTROINTESTINAL TRACT; GENE MUTATION; GENE OVEREXPRESSION; GLIOBLASTOMA; HOLOPROSENCEPHALY; HOMEOSTASIS; HUMAN; IMMUNE SYSTEM; LIVER CELL CARCINOMA; LUNG SMALL CELL CANCER; MEDULLOBLASTOMA; MOLECULAR MECHANICS; NEUROPROTECTION; NONHUMAN; PANCREAS CANCER; PROSTATE CANCER; PROTEIN FUNCTION; PROTEIN TARGETING; PSORIASIS; REVIEW; SEROTONINERGIC SYSTEM; SIGNAL TRANSDUCTION; SQUAMOUS CELL CARCINOMA; STEM CELL; STOMACH CANCER; TERATOGENICITY; TESTIS; UPREGULATION; VERATRUM;

ADULT; ANTINEOPLASTIC AGENTS, PHYTOGENIC; FEMALE; HEDGEHOG PROTEINS; HUMANS; MALE; NEOPLASMS; PHYTOTHERAPY; PLANT EXTRACTS; PSORIASIS; SIGNAL TRANSDUCTION; TERATOGENS; VERATRUM; VERATRUM ALKALOIDS;

ERINACEIDAE; LILIACEAE; VERATRUM CALIFORNICUM;

EID: 70449380987     PISSN: 00320943     EISSN: 14390221     Source Type: Journal    
DOI: 10.1055/s-0029-1185979     Document Type: Review

References (104)

1. Binns W, James LF, Shupe JL, Everett G. A congenital cyclopean-type malformation in lambs induced by maternal ingestion of a range plant, Veratrum californicum. Am J Vet Res 1963; 24: 1164-1175
2. Keeler RF. Teratogenic compounds of Veratrum californicum (Durand) X. Cyclopia in rabbits produced by cyclopamine. Teratology 1970; 3: 175-180
3. Keeler RF. Teratogenic effects of cyclopamine and jervine in rats, mice and hamsters. Proc Soc Exp Biol Med 1975; 149: 302-306
4. Bryden MM, Perry C, Keeler RF. Effects of alkaloids of Veratrum californicum on chick embryos. Teratology 1973; 8: 19-28
5. Cohen Jr MM, Shiota K. Teratogenesis of holoprosencephaly. Am J Med Genet 2002; 109: 1-15
6. Siebert JR, Cohen Jr MM, Sulik KK, Shaw C-M, Lemire RJ. Holoprosencephaly. An overview and atlas of cases. New York: Wiley-Liss; 1990
7. Keeler RF. Livestock models of human birth defects, reviewed in relation to poisonous plants. J Animal Sci 1988; 66: 2414-2427
8. Keeler RF, Binns W. Teratogenic compounds of Veratrum californicum (Durand). V. Comparison of cyclopean effects of steroidal alkaloids from the plant and structurally related compounds from other sources. Teratology 1968; 1: 5-10
9. Keeler RF. Cyclopamine and related steroidal alkaloid teratogens: their occurrence, structural relationship, and biological effects. Lipids 1978; 13: 708-715
10. Cong Y, Guo L, Yang JY, Li L, Zhou YB, Chen J,Wang JH. Steroidal alkaloids from Veratrum japonicum with genotoxicity on brain cell DNA of the cerebellum and cerebral cortex in mice. Planta Med 2007; 73: 1588-1591
11. Cong Y, Zhou YB, Chen J, Zeng YM, Wang JH. Alkaloid profiling of crude and processed Veratrum nigrum L. through simultaneous determination of ten steroidal alkaloids by HPLC-ELSD. J Pharm Biomed Anal 2008; 48: 573-578
12. Schep LJ, Schmierer DM, Fountain JS. Veratrum poisoning. Toxicol Rev 2006; 25: 73-78
13. Ma R, Ritala A, Oksman-Caldentey KM, Rischer H. Development of in vitro techniques for the important medicinal plant Veratrum californicum. Planta Med 2006; 72: 1142-1148
14. Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, Scherer SW, Tsui LC, Muenke M. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 1996; 14: 357-360
15. Chiang C, Litingung Y, Lee E, Young KE, Corden JE,Westphal H, Beachy PA. Cyclopia and defective axial patterning in mice lacking sonic hedgehog gene function. Nature 1996; 383: 407-413
16. Cooper MK, Porter JA, Young KE, Beachy PA. Teratogen-mediated inhibition of target tissue response to Shh signalling. Science 1998; 280: 1603-1607
17. Bijlsma MF, Spek CA, Peppelenbosch MP. Hedgehog: an unusual signal transducer. Bioessays 2004; 26: 387-394
18. Hooper JF, Scott MP. Communicating with hedgehogs. Nat Rev Mol Cell Biol 2005; 6: 306-317
19. Ingham PW, Placzek M. Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nat Rev Genet 2006; 7: 841-850
20. Eaton S. Multiple roles for lipids in the Hedgehog signalling pathway. Nat Rev Mol Cell Biol 2008; 9: 437-445
21. Variosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev 2008; 22: 2454-2472
22. Mann RK, Beachy PA. Novel lipid modifications of secreted protein signals. Ann Rev Biochem 2004; 73: 891-923
23. Miura GI, Treisman JE. Lipid modification of secreted signaling proteins. Cell Cycle 2006; 5: 1184-1188
24. Torroja C, Gorfinkel N, Guerrero I. Mechanisms of hedgehog gradient formation and interpretation. J Neurobiol 2005; 64: 334-356
25. Dessaud E, Yang LL, Hill K, Cox B, Ulloa F, Ribeiro A, Mynett A, Novitch BG, Briscoe J. Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism. Nature 2007; 450: 717-721
26. Panakova D, Sprong H, Marois E, Thiele C, Eaton S. Lipoprotein particles are required for Hedgehog and Wingless signaling. Nature 2005; 435: 58-65
27. BijlsmaMF, Spek CA, Zivkovic D, van deWater S, Rezaee F, Peppelenbosch MP. Repression of smoothened by patched-dependent (pro)vitamin D3 secretion. PLoS Biol 2006; 18: 1397-1410
28. Taipale J, Cooper MK, Maiti T, Beachy PA. Patched acts catalytically to suppress the activity of Smoothened. Nature 2002; 418: 892-897
29. Dennler S, André J, Alexaki I, Li A, Magnaldo T, ten Dijke P, Wang XJ, Verrecchia F, Mauviel A. Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res 2007; 67: 6981-6986
30. Pan Y, Wong B. A novel protein-processing domain in Gli2 and Gli3 differentially blocks complete protein degradation by the proteasome. J Biol Chem 2007; 282: 10846-10852
31. Fernández-Zapico ME. Primers on molecular pathways. Gli: more than just hedgehog? Pancreatology 2008; 8: 227-229
32. Chen JK, Taipale J, CooperMK, Beachy PA. Inhibition of hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 2002; 16: 2743-2748
33. Mistretta CM, Liu HX, Gaffield W, MacCallum DK. Cyclopamine and jervine in embryonic rat tongue cultures demonstrate a role for Shh signaling in taste papilla development and patterning: fungiform papillae double in number and form innovel locations in dorsal lingual epithelium. Dev Biol 2003; 254: 1-18
34. Yoo YA, Kang MH, Kim JS, Oh SC. Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-b-mediated activation of the ALK5-Smad 3 pathway. Carcinogenesis 2008; 29: 480-490
35. Taş S, Avcib O. Rapid clearance of psoriatic skin lesions induced by topical cyclopamine. Dermatology 2004; 209: 126-131
36. Bar EE, Chaudry A, Lin A, Fan X, Schreck K, MatsuiW, Piccirillo S, Vescovi AL, DiMeco F, Olivi A, Eberhart CG. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 2007; 25: 2524-2533
37. Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P,WichaMS. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006; 66: 6063-6071
38. Kumar SK, Roy I, Anchoori RK, Fazli S, Maitra A, Beachy PA, Khan SR. Targeted inhibition of hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer. Bioorg Med Chem 2008; 16: 2764-2768
39. Lees C, Howie S, Sartor BR, Satsangi J. The hedgehog signalling pathway in the gastrointestinal tract: implications for development, homeostasis, and disease. Gastroenterology 2005; 129: 1696-1710
40. Parga JA, Rodriguez-Pallares J, Blanco V, Guerra MJ, Labandeira-Garcia JL. Different effects of anti-sonic hedgehog antibodies and the hedgehog pathway inhibitor cyclopamine on generation of dopaminergic neurons from neurospheres of mesencephalic precursors. Dev Dyn 2008; 237: 909-917
41. Hashimoto M, Ishii K, Nakamura Y, Watabe K, Kohsaka S, Akazawa C. Neuroprotective effect of sonic hedgehog up-regulated in Schwann cells following sciatic nerve injury. J Neurochem 2008; 107: 918-927
42. Charytoniuk D, Porcel B, Rodríguez Gomez J, Faure H, Ruat M, Traiffort E. Sonic Hh signalling in the developing and adult brain. J Physiol Paris 2002; 96: 9-16
43. Van den Brink GR, Bleuming SA, Hardwick JCH, Schepman BL, Offerhaus GJ, Keller JJ, Nielsen C, Gaffield W, van Deventer SJ, Roberts DJ, Peppelenbosch MP. Indian hedgehog is an antagonist of Wnt signalling in colonic epithelial cell differentiation. Nature Genet 2004; 36: 277-282
44. Omenetti A, Diehl AM. The adventures of sonic hedgehog in development and repair. II. Sonic hedgehog and liver development, inflammation, and cancer. Am J Physiol Gastrointest Liver Physiol 2008; 294: G595-598
45. Szczepnya A, Hogartha CA, Younga J, Lovelanda KL. Identification of Hedgehog signalling outcomes in mouse testis development using a hanging-drop culture system. Biol Reprod 2009; 80: 258-263
46. Varas A, Carmen HL, Jaris V, Silvia M, Martínez VG, Hidalgo L, Gutiérrez-Frías C, Zapata AG, Sacedón R, Vicente A. Survival and function of human thymic dendritic cells are dependent on autocrine Hedgehog signaling. J Leukoc Biol 2008; 83: 1476-1483
47. Lavine KJ, Kovacs A, Ornitz DM. Hedgehog signalling is critical formaintenance of the adult coronary vasculature in mice. J Clin Invest 2008; 7: 2404-2414
48. Bijlsma MF, Spek AC, Peppelenbosch MP. Hedgehog turns lipoproteins into janus-faced particles. Cardiovasc Med 2006; 16: 217-220
49. Bijlsma MF, Peppelenbosch MP, Spek AC. Hedgehog morphogen in cardiovascular disease. Circulation 2006; 114: 1985-1991
50. Bijlsma MF, Leenders PJ, Janssen BJ, Peppelenbosch MP, Ten Cate H, Spek CA. Endogenous hedgehog expression contributes tomyocardial ischemia- reperfusion-induced injury. Exp Biol Med (Maywood) 2008; 233: 989-996
51. Ohba S, Kawaguchi H, Kugimiya F, Ogasawara T, Kawamura N, Saito T, Ikeda T, Fujii K, Miyajima T, Kuramochi A, Miyashita T, Oda H, Nakamura K, Takato T, Chung UI. Patched1 haploinsufficiency increases adult bonemass and modulates Gli3 repressor activity. Dev Cell 2008; 14: 689-699
52. Gesta S, Tseng Y, Kahn C. Developmental origin of fat: tracking obesity to its source. Cell 2007; 135: 366
53. Cousin W, Fontaine C, Dani C, Peraldi P. Hedgehog and adipogenesis: Fat and fiction. Biochimie 2007; 89: 1447-1453
54. Suh J, Gao X, McKay J, McKay R, Salo Z, Graff J. Hedgehog signaling plays a conserved role in inhibiting fat formation. Cell Metab 2006; 3: 25-34
55. Fontaine C, Cousin W, Plaisant M, Dani C, Peraldi P. Hedgehog signaling alters adipocyte maturation of human mesenchymal stem cells. Stem Cells 2008; 26: 1037-1046
56. Cousin W, Dani C, Peraldi P. Inhibition of the anti-adipogenic hedgehog signaling pathway by cyclopamine does not trigger adipocyte differentiation. Biochem Biophys Res Commun 2006; 349: 799-803
57. Horst G, Sips H, Lowik C, Karperien M. Hedgehog stimulates only osteoplastic differentiation of undifferentiated Ks483 cells. Bone 2003; 33: 899-910
58. Martin PI, Lane J, Pouliot L, Gains M, Stejskal R, Smith Y, Galdes A, Green J. Increases in adipose and total body weight, but not in lean body mass, associated with subcutaneous administration of sonic hedgehog-Ig fusion protein to mice. Drug DevRes 2002; 57: 107-114
59. Goodrich L, Milenkovic M, Higgins K, Scott M. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 1997; 277: 1109-1113
60. Gorlin R. Nevoid basal cell cacrinoma syndrome. Medicine (Baltimore) 1987; 66: 98-113
61. Buhman K,Wang L, Tang Y, Swietlicki E, Kennedy S, Xie Y, Liu Z, Burkly L, Levin M, Rubin D, Davidson N. Inhibition of Hedgehog signaling protects adult mice from diet-induces weight gain. J Nutr 2004; 134: 2979-2984
62. Wang LC, Nassir F, Liu ZY, Ling L, Kuo F, Crowell T, Olson D, Davidson NO, Burkly LC. Disruption of hedgehog signalling reveals a novel role in intestinal morphogenesis and intestinal-specific lipid metabolism in mice. Gastroenterology 2002; 122: 469-482
63. Beckers L, Heeneman S,Wang L, Burkly LC, Rouch MMJ, Davidson NO, Gijbels MJ, de Winther MP, Daemen MJ, Lutgens E. Disruption of hedgehog signalling in ApoE-/- mice reduces plasma lipid levels, but increases atherosclerosis due to enhanced lipid uptake by macrophages. J Pathol 2007; 212: 420-428
64. Li Z, Zhang H, Denhradt L, Liu L, Zhou H, Lan Z. Reduced white fatmass in adult mice bearing a truncated Patched 1. Int J Biol Sci 2008; 4: 29-36
65. Watkins DN, Peacock CD. Hedgehog signalling in foregut malignancy. Biochem Pharmacol 2004; 68: 1055-1060
66. Datta S, Datta MW. Sonic Hedgehog signaling in advanced prostate cancer. Cell Mol Life Sci 2006; 63: 435-448
67. Lauth M, Toftgård R. Non-canonical activation of GLI transcription factors. Cell Cycle 2007; 6: 2458-2463
68. Bailey JM, Singh PK, Hollingsworth MA. Cancer metastasis facilitated by developmental pathways: sonic hedgehog, notch, and bone morphogenic proteins. J Cell Biochem 2007; 102: 829-839
69. Tremblay MR, Nevalainen M, Nair SJ, Porter JR, Castro AC, Behnke ML, Yu LC, Hagel M, White K, Faia K, Grenier L, Campbell MJ, Cushing J, Woodward CN, Hoyt J, Foley MA, ReadMA, Sydor JR, Tong JK, Palombella VJ, Mc-Govern K, Adams J. Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists. J Med Chem 2008; 51: 6646-6649
70. Yanai K, Nagai S, Wada J, Yamanaka N, Nakamura M, Torata N, Noshiro H, TsuneyoshiM, Tanaka M, Katano M. Hedgehog signaling pathway is a possible therapeutic target for gastric cancer. J Surg Oncol 2007; 95: 55-62 (Pubitemid 46122719)
71. Abe Y, Oda-Sato E, Tobiume K, Kawauchi K, Taya Y, Okamoto K, Oren M, Tanaka N. Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2. Proc Natl Acad Sci USA 2008; 105: 4838-4843
72. Peacock CD,Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, Devereux WL, Rhodes JT, Huff CA, Beachy PA, Watkins DN, Matsui W. Hedgehog signalingmaintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci USA 2007; 104: 4048-4053
73. Geng L, Cuneo KC, Cooper MK, Wang H, Sekhar K, Fu A, Hallahan DE. Hedgehog signaling in the murine melanoma microenvironment. Angiogenesis 2007; 10: 259-267
74. James LF, Panter KE, Gaffield W, Molyneux RJ. Biomedical applications of poisonous plant research. J Agric Food Chem 2004; 52: 3211-3230
75. He J, Sheng T, Stelter AA, Li C, Zhang X, Sinha M, Luxon BA, Xie J. Suppressing Wnt signaling by the Hedgehog pathway through sFRP-1. J Biol Chem 2006; 281: 35598-35602
76. Hatsell S, Frost AR. Hedgehog signaling in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia 2007; 12: 163-173
77. Tada M, Kanai F, Tanaka Y, Tateishi K, Ohta M, Asaoka Y, Seto M, Muroyama R, Fukai K, Imazeki F, Kawabe T, Yokosuka O, Omata M. Downregulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma. Clin Cancer Res 2008; 14: 3768-3776
78. Gudjonsson JE, Aphale A, Grachtchouk M, Ding J, Nair RP, Wang T, Voorhees JJ, Dlugosz AA, Elder JT. Lack of evidence for activation of the hedgehog pathway in psoriasis. J Invest Dermatol 2009; 129: 635-640
79. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nature Rev 2008; 8: 743-754
80. Rubin LL, de Sauvage FJ. Targeting the Hedgehog pathway in cancer. Nature Rev 2006; 5: 1026-1033
81. Lupi O. Correlations between the Sonic Hedgehog pathway and basal cell carcinoma. Int J Dermatol 2007; 46: 1113-1117
82. Stecca B, Mas C, Altaba AR. Interference with HH-GLI signaling inhibits prostate cancer. Trends Mol Med 2005; 11: 199-203
83. Clark PA, Treisman DM, Ebben J, Kuo JS. Developmental signaling pathways in brain tumor-derived stem-like cells. Dev Dyn 2007; 236: 3297-3308
84. Ehtesham M, Sarangi A, Valadez JG, Chanthaphaychith S, Becher MW, Abel TW, Thompson RC, Cooper MK. Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells. Oncogene 2007; 26: 5752-5761
85. Nishimaki H, Kasai K, Kozaki K, Takeo T, Ikeda H, Saga S, Nitta M, Itoh G. A role of activated Sonic hedgehog signaling for the cellular proliferation of oral squamous cell carcinoma cell line. Biochem Biophys Res Commun 2004; 314: 313-320
86. Katoh Y, Katoh M. Hedgehog signaling pathway and gastrointestinal stem cell signaling network. Int J Mol Med 2006; 18: 1019-1023
87. Yamazaki M, Nakamura K, Mizukami Y, Ii M, Sasajima J, Sugiyama Y, Nishikawa T, Nakano Y, Yanagawa N, Sato K, Maemoto A, Tanno S, Okumura T, Karasaki H, Kono T, FujiyaM, Ashida T, Chung DC, Kohgo Y. Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells. Cancer Sci 2008; 99: 1131-1138
88. Lee CJ, Dosch J, Simeone DM. Pancreatic cancer stem cells. J Clin Oncol 2008; 26: 2806-2812
89. Feldmann G, Habbe N, Dhara S, Bisht S, Alvarez H, Fendrich V, Beaty R, Mullendore M, Karikari C, Bardeesy N, Ouellette MM, Yu W, Maitra A. Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut 2008; 57: 1420-1430
90. Shafaee Z, Schmidt H, Du W, PosnerM,Weichselbaum R. Cyclopamine increases the cytotoxic effects of paclitaxel and radiation but not cisplatin and gemcitabine in Hedgehog expressing pancreatic cancer cells. Cancer Chemother Pharmacol 2006; 58: 765-770
91. Jinawath A, Akiyama Y, Sripa B, Yuasa Y. Dual blockade of the Hedgehog and ERK1/2 pathways coordinately decreases proliferation and survival of cholangiocarcinoma cells. J Cancer Res Clin Oncol 2007; 133: 271-278
92. Watkins DN, Berman DM, Burkholder SG, Wang B. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003; 422: 313-317
93. Shaw G, Prowse DM. Inhibition of androgen-independent prostate cancer cell growth is enhanced by combination therapy targeting Hedgehog and ErbB signaling. Cancer Cell Int 2008; 18: 8-13
94. Fendrich V, Waldmann J, Esni F, Ramaswamy A, Mullendore M, Buchholz M, Maitra A, Feldmann G. Snail and Sonic Hedgehog activation in neuroendocrine tumors of the ileum. Endocr Relat Cancer 2007; 14: 865-874
95. Iorio MV, Casalini P, Tagliabue E, Ménard S, Croce CM. MicroRNA profiling as a tool to understand prognosis, therapy response and resistance in breast cancer. Eur J Cancer 2008; 44: 2753-2759
96. Mehta RG, Naithani R, Huma L, Hawthorne M, Moriarty RM, McCormick DL, Steele VE, Kopelovich L. Efficacy of chemopreventive agents in mouse mammary gland organ culture (MMOC) model: a comprehensive review. Curr Med Chem 2008; 15: 2785-2825
97. Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M, Kuroki S, Katano M. Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res 2004; 64: 6071-6074
98. Zhang X, Harrington N, Moraes RC, Wu MF, Hilsenbeck SG, Lewis MT. Cyclopamine inhibition of human breast cancer cell growth independent of Smoothened (Smo). Breast Cancer Res Treat 2009; 115: 505-521
99. Kasper M, Jaks V, Fiaschi M, Toftgård R. Hedgehog signalling in breast cancer. Carcinogenesis 2009; 30: 903-911
100. Endo H, Momota Y, Oikawa A, Shinkai H. Psoriatic skin expresses the transcription factor Gli1: possible contribution of decreased neurofibromin expression. Br J Dermatol 2006; 154: 619-623
101. Kuenzli S, Sorg O, Saurat JH. Cyclopamine, Hedgehog and psoriasis. Dermatology 2004; 209: 81-83
102. McFerren MA. Useful plants of dermatology. VIII. The false hellebore (Veratrum californicum). J Am Acad Dermatol 2006; 54: 718-720
103. Xie J. Implications of hedgehog signaling antagonists for cancer therapy. Acta Biochim Biophys Sin (Shanghai) 2008; 40: 670-680
104. Zhang J, Garrossian M, Gardner D, Garrossian A, Chang YT, Kim YK, Chang CW. Synthesis and anticancer activity studies of cyclopamine derivatives. Bioorg Med Chem Lett 2008; 18: 1359-1363