Cyclopamine, a naturally occurring alkaloid, and its analogues may find wide applications in cancer therapy

Current Topics in Medicinal Chemistry

Volumn 13, Issue 17, 2013, Pages 2208-2215

  Ma, Haikuo ^a   Li, Huan Qiu ^a   Zhang, Xiaohu ^a  

^a SOOCHOW UNIVERSITY   (China)

Author keywords

Antagonist; Cancer therapy; Cyclopamine; Smoothened; Sonic hedgehog; Steroidal alkaloid

Indexed keywords

3 KETO N AMINOETHYL AMINOCAPROYL DIHYDROCINNAMOYL CYCLOPAMINE; ALKALOID DERIVATIVE; BEVACIZUMAB; CARBOHYDRATE DERIVATIVE; CYCLOPAMINE; DESMETHYLVERAMILINE; ESTRONE; EXO CYCLOPAMINE; GEMCITABINE; IPI 609; JERVINE; LACTAM DERIVATIVE; MESSENGER RNA; PF 0449913; PLACEBO; PRASTERONE; PROGESTERONE; PYRAZOLE DERIVATIVE; SARIDEGIB; SMOOTHENED PROTEIN; SOLASODINE; SONIC HEDGEHOG PROTEIN; SONIDEGIB; TEMOZOLOMIDE; TETRAHYDROJERVINE; TOMATIDINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VERAMILINE; VERATRAMINE; VISMODEGIB;

ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; ARTICLE; BASAL CELL CARCINOMA; CANCER INHIBITION; CHEMICAL MODIFICATION; CHONDROSARCOMA; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG SOLUBILITY; DRUG STABILITY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TOLERABILITY; GENE MUTATION; HUMAN; MEDULLOBLASTOMA; MYELOFIBROSIS; NEOPLASM; NONHUMAN; OVARY CANCER; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC);

ALKALOIDS; ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; MOLECULAR STRUCTURE; NEOPLASMS; VERATRUM ALKALOIDS;

EID: 84887966649     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/15680266113139990153     Document Type: Article

References (63)

1. Keeler, R. F.; Binns, W. Teratogenic compounds of Veratrum californicum (Durand). II. Production of ovine fetal cyclopia by fractions and alkaloid preparations. Can. J. Biochem, 1966, 44, 829-838.
2. Keeler, R. F. Teratogenic compounds of Veratrum californicum (Durand). VI. The structure of cyclopamine. Phytochemistry, 1969, 8, 223-225.
3. Binns, W.; James, L. F.; Shupe, J. L.; Everett, G. A congenital cyclopian-type malformation in lambs induced by maternal ingestion of a range plant, Veratrum californicum. Am. J. Vet. Res, 1963, 24, 1164-1175.
4. Keeler, R. F.; Binns, W. Teratogenic compounds of Veratrum californicum (Durand). V. Comparison of cyclopian effects of steroidal alkaloids from the plant and structurally related compounds from other sources. Teratology, 1968, 1, 5-10.
5. Keeler, R. F. Cyclopamine and related steroidal alkaloid teratogens: Their occurrence, structural relationship and biologic effects. Lipids, 1978, 13, 708-715.
6. Cooper, M. K.; Porter, J. A.; Young, K. E.; Beachy, P. A. Teratogenmediated inhibition of target tissue response to Shh signaling. Science, 1998, 280, 1603-1607.
7. Incardona, J. P.; Gaffield, W.; Kapur, R. P.; Roelink, H. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development, 1998, 125, 3553-3562.
8. Ruizi Altaba, A.; Sanchez, M. P.; Dahmane, N. Gli and Hedgehog in cancer: tumours, embryos and stem cells. Nat. Rev. Cancer, 2000, 2, 361-372.
9. Hooper, J. E.; Scott, M. P. Communicating with Hedgehogs. Nat. Rev. Mol. Cell Biol, 2005, 6, 306-317.
10. Ingham, P. W.; McMahon, A. P. Hedgehog signaling in animal development: paradigms and principles. Genes. Dev., 2001, 15, 3059-3087.
11. Chen, J. K.; Taipale, J.; Cooper, M. K.; Beachy, P. A. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes. Dev., 2002, 16, 2743-2748.
12. S. J. Scales, F. J. de Sauvage, Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol. Sci, 2008, 30, 303-312.
13. Hahn, J.; Wicking, C.; Zaphiropoulous, P.; Gailini, M.; Shanley, S.; Chidambaram, A.; Vorechovsky, I.; Holmberg, E.; Unden, A.; Gillies, S.; Negus, K.; Smyth, I.; Pressman, C.; Leffell, D.; Gerrard, B.; Goldstein, A.; Dean, M.; Toftgard, R.; Chenevix-Trench, G.; Wainwright, B.; Bale, A. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell, 1996, 85, 841-851.
14. Johnson, R.; Rothman, A.; Xie, J.; Goodrich, L.; Bare, J.; Bonifas, J.; Quinn, A.; Myers, R.; Cox, D.; Epstein, E.; Scott, M. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science, 1996, 272, 1668-1671.
15. di Magliano, M. P.; Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nat. Rev. Cancer, 2003, 3, 903-911.
16. Beachy, P. A.; Karhadkar, S. S.; Berman, D. M. Tissue repair and stem cell renewal in carcinogenesis. Nature, 2004, 432, 324-331.
17. Dahmane, N.; Lee, J.; Robins, P.; Heller, P.; Ruizi Altaba, A. Activation of the transcription factor Gli1 and the sonic Hedgehog signaling pathway in skin tumours. Nature, 1997, 389, 876-881.
18. Hutchin, M. E.; Kariapper, M. S. T.; Gratchtchouk, M.; Wang, A.; Wei, L.; Cummings, D.; Liu, J.; Michael, L. R.; Glick, A.; Dlugosz, A. A. Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: Conditional skin tumorigenesis recapitulates the hair growth cycle. Genes. Dev., 2004, 19, 214-224.
19. 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.
20. Berman, D. M.; Karhadkar, S. S.; Maitra, A.; Montes de Oca, R.; Gerstenblith, M. R.; Briggs, K.; Parker, A. R.; Shimada, Y.; Eshleman, J. R.; Watkins, D. N.; Beachy, P. A. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumors. Nature, 2003, 425, 846-851.
21. Goodrich, L. V.; Scott, M. P. Hedgehog and Patched in neural development and disease. Neuron, 1998, 21, 1243-1257.
22. Stecca, B.; Mas., C.; Clement, V.; Zbinden, M.; Correa, R.; Piguet, V.; Beermann, F.; Ruiz, A. Melanomas require Hedgehog-Gli signaling regulated by interactions between Gli1 and the RASMEK/AKT pathways. Proc. Natl. Acad. Sci. USA, 2007, 104, 5895-5900.
23. Thayer, S. P.; Pasca di Magliano, M.; Heiser, P. W.; Nielsen, C. M.; Roberts, D. J.; Lauwers, G. Y.; Qi, Y. P.; Gysin, S.; Fernandezdel Castillo, C.; Yajnik, V.; Antoniu, B.; McMahon, M.; Warshaw, A. L.; Hebrok, M. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature, 2003, 425, 851-856.
24. Karhadkar, S. S.; Bova, G. S.; Abdallah, N.; Dhara, S.; Gardner, D.; Maitra, A.; Isaacs, J. T.; Berman, D. M.; Beachy, P. A. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature, 2004, 431, 707-712.
25. Watkins, D. N.; Berman, D. M.; Burkholder, S. G.; Wang, B.; Beachy, P. A.; Baylin, S. B. Hedgehog signaling within airway epithelial progenitors and in small-cell lung cancer. Nature, 2003, 422, 313-317.
26. Berman, D. M.; Karhadkar, S. S.; Hallahan, A. R.; Pritchard, J. I.; Eberhart, C. G.; Watkins, D. N.; Chen, J. K.; Cooper, M. K.; Taipale, J.; Olson, J. M.; Beachy, P. A. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science, 2002, 297, 1559-1561.
27. Dahmane, N.; Sanchez, P.; Gitton, Y.; Palma, V.; Sun, T.; Beyna, M.; Weiner, H.; Ruiz i Altaba, A. The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development, 2001, 128, 5201-5212.
28. Sanchez, P.; Ruiz i Altaba, A. In vivo inhibition of endogenous brain tumors through systemic interference of Hedgehog signaling in mice. Mech. Dev., 2005, 122, 223-230.
29. Keeler, R. F. Teratogenic compounds in Veratrum californicum. IX. Structure-activity relation. Teratology, 1970, 3, 169-173.
30. S. R. Wilson, M. F. Strand, A. Krapp, F. Rise, D. Petersen; S. Krauss. Hedgehog antagonist cyclopamine isomerizes to less potent forms when acidified. J. Pharm. Biomed. Anal, 2010, 52, 707-713.
31. Incardona, J. P.; Gaffield, W.; Lange, Y.; Cooney, A.; Pentchev, P. G.; Liu, S.; Watson, J. A.; Kapur, R. P.; Roelink, H. Cyclopamine inhibition of sonic Hedgehog signal transduction is not mediated through effects on cholesterol transport. Dev. Biol, 2000, 224, 440-452.
32. Winkler, J.; Isaacs, A.; Holderbaum, L.; Tatard, V.; Dahmane, N. Design and synthesis of inhibitors of Hedgehog signaling based on the alkaloid cyclopamine. Org. Lett, 2009, 11, 2824-2827.
33. Zhang, Z.; Baubet, V.; Ventocilla, C.; Xiang, C.; Dahmane, N.; Winkler, J. Stereoselective synthesis of F-ring saturated estronederived inhibitors of Hedgehog signaling based on cyclopamine. Org. Lett, 2011, 13, 4786-4789.
34. Isaacs, A.; Xiang, C.; Baubet, V.; Dahmane, N.; Winkler, J. Studies directed toward the elucidation of the pharmacophore of steroidbased Sonic Hedgehog signaling inhibitors. Org. Lett, 2011, 13, 5140-5143.
35. Winkler, J.; Isaacs, A.; Xiang, C.; Baubet, V.; Dahmane, N. Design, synthesis, and biological evaluation of estrone-derived Hedgehog signaling inhibitors. Tetrahedron, 2011, 67, 10261-10266.
36. Chen, J. K.; Taipale, J.; Young, K. E.; Maiti, T.; Beachy, P. A. Small molecule modulation of Smoothened activity. Proc. Natl. Acad. Sci. USA, 2002, 99, 14071-14076.
37. Guerlet, G.; Spangenberg, T.; Mann, A.; Faure, H.; Ruat, M. Synthesis and biological evaluation of desmethylveramiline, a micromolar Hedgehog inhibitor. Bioorg. Med. Chem. Lett, 2011, 21, 2608-2612.
38. Giannis, A.; Heretsch, P.; Sarli, V.; StoBel, A. Synthesis of cyclopamine using a biomimetic and diastereoselective approach. Angew. Chem. Int. Ed, 2009, 48, 7911-7914.
39. Heretsch, P.; Büttner, A.; Tzagkaroulaki, L.; Zahn, Z.; Kirchner, B.; Giannis, A. Exo-Cyclopamine-a stable and potent inhibitor of Hedgehog-signaling. Chem. Commun, 2011, 47, 7362-7364.
40. Beachy, P. A. Regulators of the Hedgehog pathway, compostitions and uses related thereto. WO01/27135A2, April 19, 2001.
41. Mahindroo, N.; Punchihewa, C.; Fujii, N. Hedgehog-Gli signaling pathway inhibitors as anticancer agents. J. Med. Chem, 2009, 52, 3829-3845.
42. Taipale, J.; Chen, J. K.; Cooper, M. K.; Wang, B. L.; Mann, R. K.; Milenkovic, L.; Scott, M. P.; Beachy, P. A. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature, 2000, 406, 1005-1009.
43. Zhang, J.; Garrossian, M.; Gardner, D.; Garrossian, A.; Chang, Y. T.; Kim, Y. K.; Chang, C. W. Synthesis and anticancer activity studies of cyclopamine derivatives. Bioorg. Med. Chem. Lett, 2008, 18, 1359-1363.
44. Goff, R. D.; Thorson, J. S. Enhancement of cyclopamine via conjugation with nonmetabolic sugars. Org. Lett, 2012, 14, 2454-2457.
45. Kumar, S. K.; Roy, I.; Anchoori, R. K.; Fazli, S.; Maitra, A.; Beachy, P. A.; Khan, S. R. Targeted inhibition of Hedgehog signaling by cyclopamine prodrugs for advanced prostate cancer. Bioorg. Med. Chem, 2008, 16, 2764-2768.
46. Hamon, F.; Renoux, B.; Chadéneau, C.; Muller, J.-M.; Papot, S. Study of a cyclopamine glucuronide prodrug for the selective chemotherapy of glioblastoma. Eur. J. Med. Chem, 2010, 45, 1678-1682.
47. Renoux, B.; Legigan, T.; Bensalma, S.; Chadéneau, C.; Muller, J.-M.; Papot, S. A new cyclopamine glucuronide prodrug with improved kinetics of drug release. Org. Biomol. Chem, 2011, 9, 8459-8464.
48. Tremblay, M.; Nevalainen, M.; Nair, S.; Porter, J.; Castro, A.; Behnke, M.; Yu, L.; Hagel, M.; White, K.; Faia, K.; Grenier, L.; Campbell, M.; Cushing, J.; Woodward, C.; Hoyt, J.; Foley, M.; Read, M.; Sydor, J.; Tong, J.; Palombella, V.; McGovern, K.; Adams, J. Semisynthetic cyclopamine analogues as potent and orally bioavailable Hedgehog pathway antagonists. J. Med. Chem, 2008, 51, 6646-6649.
49. Tremblay, M.; Lescarbeau, A.; Grogan, M.; Tan, E.; Lin, G.; Austad, B.; Yu, L.; Behnke, M.; Nair, S.; Hagel, M.; White, K.; Conley, J.; Manna, J.; Alvarez-Diez, T.; Hoyt, J.; Woodward, C.; Sydor, J.; Pink, M.; MacDougall, J.; Campbell, M.; Cushing, J.; Ferguson, J.; Curtis, M.; McGovern, K.; Read, M.; Palombella, V.; Adams, J.; Castro, A. Discovery of a potent and orally active Hedgehog pathway antagonist (IPI-926). J. Med. Chem, 2009, 52, 4400-4418.
50. McCann, C. K.; Growdon, W. B.; Kulkarni-Datar, K.; Curley, M. D.; Friel, A. M.; Proctor, J. L.; Sheikh, H.; Deyneko, I.; Ferguson, J. A.; Vathipadiekal, V.; Birrer, M.; Borger, D. R.; Mohapatra, G.; Zukerberg, L. R.; Foster, R.; MacDougall, J. R.; Rueda, B. R. Inhibition of Hedgehog signaling antagonizes serous ovarian cancer growth in a primary xenograft model. PLos One, 2011, 6 (11), e28077.
51. Yauch, R. L.; Gould, S. E.; Scales, S. J.; Tang, T.; Tian, H.; Ahn, C. P.; Marshall, D.; Fu, L.; Januario, T.; Kallop, D.; Nannini-Pepe, M.; Kotkow, K.; Marsters, J. C.; Rubin, L. L.; de Sauvage, F. J. A paracrine requirement for hedgehog signalling in cancer. Nature, 2008, 455, 406-410.
52. Lee, M. J.; Hatton, B. A.; Villavicencio, E. H.; Khanna, P. C.; Friedman, S. D.; Ditzler, S.; Pullar, B.; Robison, K.; White, K. F.; Tunkey, C.; LeBlank, M.; Randolph-Habecker, J.; Knoblaugh, S. E.; Hansen, S.; Richards, A.; Wainwright, B. J.; McGovern, K.; Olson, J. M. Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model. Proc. Natl. Acad. Sci. USA, 2012, 109, 7859-7864.
53. Yauch, R. L.; Dijkgraaf, G. J.; Alicke, B.; Januario, T.; Ahn, C. P.; Holcomb, T.; Pujara, K.; Stinson, J.; Callahan, C. A.; Tang, T.; Bazan, J. F.; Kan, Z.; Seshagiri, S.; Hann, C. L.; Gould, S. E.; Low, J. A.; Rudin, C. M.; de Sauvage, F. J. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science, 2009, 326, 572-574.
54. Buonamici S, Williams, J.; Morrissey, M.; Wang, A.; Guo, R.; Vattay, A.; Hsiao, K.; Yuan, J.; Green, J.; Ospina, B.; Yu, Q.; Ostrom, L.; Fordjour, P.; Anderson, D. L.; Monahan, J. E.; Kelleher, J. F.; Peukert, S.; Pan, S.; Wu, X.; Maira, S.; Garcia-Echeverria, C.; Briggs, K. J.; Watkins, D. N.; Yao Y.; Lengauer, C.; Warmuth, M.; Sellers, W.; Dorsch, M. Interfering with resistance to Smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci. Transl. Med, 2010, 2, 51-70.
55. Infinity Pharmaceuticals press release: http://phx. corporateir. net/phoenix. zhtml?c=121941&p=irolnewsArticle&ID=1705831 &highlight=.
56. Curis Pharmaceuticals press release: http://investors. curis. com/releasedetail. cfm?ReleaseID=643756.
57. Mahindroo, N.; Punchihewa, C.; Fujii, N. Hedgehog-Gli Signaling Pathway Inhibitors as Anticancer Agents. J. Med. Chem, 2009, 52, 3829-3845.
58. Weiss, G. J.; Mita, A. C.; Von Hoff, D. The Hedgehog knows many tricks. Curr. Drug Targets, 2011, 12, 2091-2095.
59. Gould, A.; Missailidis, S. Targeting the hedgehog pathway: the development of Cyclopamine and the development of anti-cancer drugs targeting the hedgehog pathway. Mini-Rev. Med. Chem, 2011, 11, 200-213.
60. Li, Y.; Maitah, M.; Ahmad, A.; Kong, D.; Bao, B.; Sarkar, F. H. Targeting the hedgehog signaling pathway for cancer therapy. Expert Opin. Ther. Tar, 2012, 16, 49-66.
61. Lin, T.; Matsui, W. Hedgehog pathway as a drug target: Smoothened inhibitors in development. OncoTarget. Ther, 2012, 5, 47-58.
62. Yun, J.; Kim, H. R.; Park, H.; Kim, S. K.; Lee, J. Small molecule inhibitors of the hedgehog signaling pathway for the treatment of cancer. Arch. Pharm. Res, 2012, 35, 1317-1333.
63. Hassounah, N. B.; Bunch, T. A.; McDermott, K. M. Molecular pathways, the role of primary cilia in cancer progression and therapeutics with a focus on hedgehog signaling. Clin. Cancer Res, 2012, 18, 2429-2435.