Inhibition of hedgehog/Gli signaling by botanicals: A review of compounds with potential hedgehog pathway inhibitory activities

Current Cancer Drug Targets

Volumn 13, Issue 5, 2013, Pages 580-595

  Drenkhahn, Sara K ^a   Jackson, Glenn A ^a,b   Slusarz, Anna ^a,c   Starkey, Nicholas J E ^a   Lubahn, Dennis B ^a  

^a UNIVERSITY OF MISSOURI   (United States)

^b Department of Veterinary Technology   (United States)

^c University of Missouri   (United States)

Author keywords

Botanicals; Cancer; Dietary chemoprevention; Gli; Hedgehog signaling; Nutraceuticals

Indexed keywords

16 ACETYLGITOXIGENIN B DGLUCOSYL (1A4) B D THEVETOSIDE; 16 FORMYLGITOXIGENIN B D THEVETOSIDE; 5,6 DIHYDROXYACRYRIFLAVIN A; 6 HYDROXYSTAUROSPORINONE; ACOSCHIMPEROSIDE P; ALPHITOLIC ACID; APIGENIN; ARCRYAFLAVIN C; BETULIC ACID; COLUBRINIC ACID; CURCUMIN; CYCLOPAMINE; DIGITOXIGENIN B D GLUCOSYL (1A4) B D THEVETOSIDE; DIGITOXIN B D DIGITALOSIDE; DOCETAXEL; EPIGALLOCATECHIN GALLATE; GENISTEIN; GITOXIGENIN B D SARMENTOSIDE; HERBACEOUS AGENT; PHYSALIN B; PHYSALIN F; QUERCETIN; RESVERATROL; STAUROSPORINONE; TAEPEENIN D; UNCLASSIFIED DRUG; UNINDEXED DRUG; VISMODEGIB; ZERUMBONE; ZERUMBONE EPOXIDE;

ALZHEIMER DISEASE; APOPTOSIS; AYURVEDA; BASAL CELL NEVUS SYNDROME; BIOAVAILABILITY; CANCER INHIBITION; CARDIOVASCULAR DISEASE; CHEMOPROPHYLAXIS; CHINESE MEDICINE; CHONDROSARCOMA; COLON CANCER; GENE EXPRESSION; HEAD AND NECK CANCER; HEDGEHOG GLI SIGNALING; HUMAN; ISCHEMIA; LUNG CANCER; MEDULLOBLASTOMA; NEOPLASM; NONHUMAN; PANCREAS CANCER; PROSTATE CANCER; PROTEIN EXPRESSION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; REVIEW; SIGNAL TRANSDUCTION; WESTERN BLOTTING;

ANIMALS; ANTINEOPLASTIC AGENTS; BIOLOGICAL PRODUCTS; HEDGEHOG PROTEINS; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASMS; PHYTOTHERAPY; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS;

EID: 84888115221     PISSN: 15680096     EISSN: 18735576     Source Type: Journal    
DOI: 10.2174/15680096113139990003     Document Type: Review

References (197)

1. Chen, M.; Feuerstein, M. A.; Levina, E.; Baghel, P. S.; Carkner, R. D.; Tanner, M. J.; Shtutman, M.; Vacherot, F.; Terry, S.; de la Taille, A., Buttyan, R. Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells. Mol. Cancer 2010, 9, 89.
2. Huang, S.; Yang, L.; An, Y.; Ma, X.; Zhang, C.; Xie, G.; Chen, Z. Y.; Xie, J., Zhang, H. Expression of hedgehog signaling molecules in lung cancer. Acta. Histochem. 2011, 113 (5), 564-569.
3. Kelleher, F. C. Hedgehog signaling and therapeutics in pancreatic cancer. Carcinogenesis 2011, 32 (4), 445-451.
4. Kiesslich, T., Neureiter, D. Advances in targeting the Hedgehog signaling pathway in cancer therapy. Expert Opin. Ther. Targets. 2012, 16 (2), 151-156.
5. Li, X.; Ma, Q.; Duan, W.; Liu, H.; Xu, H., Wu, E. Paracrine sonic hedgehog signaling derived from tumor epithelial cells: a key regulator in the pancreatic tumor microenvironment. Crit. Rev. Eukaryot. Gene Expr. 2012, 22 (2), 97-108.
6. Merchant, J. L.; Saqui-Salces, M., El-Zaatari, M. Hedgehog signaling in gastric physiology and cancer. Prog. Mol. Biol. Transl. Sci. 2010, 96, 133-156.
7. Park, K. S.; Martelotto, L. G.; Peifer, M.; Sos, M. L.; Karnezis, A. N.; Mahjoub, M. R.; Bernard, K.; Conklin, J. F.; Szczepny, A.; Yuan, J.; Guo, R.; Ospina, B.; Falzon, J.; Bennett, S.; Brown, T. J.; Markovic, A.; Devereux, W. L.; Ocasio, C. A.; Chen, J. K.; Stearns, T.; Thomas, R. K.; Dorsch, M.; Buonamici, S.; Watkins, D. N.; Peacock, C. D., Sage, J. A crucial requirement for Hedgehog signaling in small cell lung cancer. Nat. Med. 2011, 17 (11), 1504-1508.
8. Ruiz I Altaba, A. Hedgehog signaling and the Gli code in stem cells, cancer, and metastases. Sci. Signal. 2011, 4 (200), pt9.
9. Velcheti, V., Govindan, R. Hedgehog signaling pathway and lung cancer. J. Thorac. Oncol. 2007, 2 (1), 7-10.
10. Yang, Y.; Tian, X.; Xie, X.; Zhuang, Y.; Wu, W., Wang, W. Expression and regulation of hedgehog signaling pathway in pancreatic cancer. Langenbecks Arch. Surg. 2010, 395 (5), 515-525.
11. Lorusso, P. M.; Jimeno, A.; Dy, G.; Adjei, A.; Berlin, J.; Leichman, L.; Low, J. A.; Colburn, D.; Chang, I.; Cheeti, S.; Jin, J. Y., Graham, R. A. Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors. Clin. Cancer Res. 2011, 17 (17), 5774-5782.
12. Graham, R. A.; Lum, B. L.; Cheeti, S.; Jin, J. Y.; Jorga, K.; Von Hoff, D. D.; Rudin, C. M.; Reddy, J. C.; Low, J. A., Lorusso, P. M. Pharmacokinetics of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding. Clin. Cancer Res. 2011, 17 (8), 2512-2520.
13. De Smaele, E.; Ferretti, E., Gulino, A. Vismodegib, a small-molecule inhibitor of the hedgehog pathway for the treatment of advanced cancers. Curr. Opin. Investig. Drugs 2010, 11 (6), 707-718.
14. Rudin, C. M.; Hann, C. L.; Laterra, J.; Yauch, R. L.; Callahan, C. A.; Fu, L.; Holcomb, T.; Stinson, J.; Gould, S. E.; Coleman, B.; LoRusso, P. M.; Von Hoff, D. D.; de Sauvage, F. J., Low, J. A. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N. Engl. J. Med. 2009, 361 (12), 1173-1178.
15. Von Hoff, D. D.; LoRusso, P. M.; Rudin, C. M.; Reddy, J. C.; Yauch, R. L.; Tibes, R.; Weiss, G. J.; Borad, M. J.; Hann, C. L.; Brahmer, J. R.; Mackey, H. M.; Lum, B. L.; Darbonne, W. C.; Marsters, J. C., Jr.; de Sauvage, F. J., Low, J. A. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N. Engl. J. Med. 2009, 361 (12), 1164-1172.
16. Von Hoff, D. D.; Lorusso, P. M.; Rudin, C. M.; Reddy, J. C.; Yauch, R. L.; Tibes, R.; Weiss, G. J.; Borad, M. J.; Hann, C. L.; Brahmer, J. R.; Mackey, H. M.; Lum, B. L.; Darbonne, W. C.; Marsters, J. C., Jr.; de Sauvage, F. J., Low, J. A. Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma. N. Engl. J. Med. 2009.
17. 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 (5952), 572-574.
18. 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. M.; Garcia-Echeverria, C.; Briggs, K. J.; Watkins, D. N.; Yao, Y. M.; Lengauer, C.; Warmuth, M.; Sellers, W. R., Dorsch, M. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci. Transl. Med. 2010, 2 (51), 51ra70.
19. Dijkgraaf, G. J.; Alicke, B.; Weinmann, L.; Januario, T.; West, K.; Modrusan, Z.; Burdick, D.; Goldsmith, R.; Robarge, K.; Sutherlin, D.; Scales, S. J.; Gould, S. E.; Yauch, R. L., de Sauvage, F. J. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 2011, 71 (2), 435-444.
20. Binns, W.; James, L. F.; Keeler, R. F., Balls, L. D. Effects of teratogenic agents in range plants. Cancer Res. 1968, 28 (11), 2323-2326.
21. Nusslein-Volhard, C., Wieschaus, E. Mutations affecting segment number and polarity in Drosophila. Nature 1980, 287 (5785), 795-801.
22. Krauss, S.; Concordet, J. P., Ingham, P. W. A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell 1993, 75 (7), 1431-1444.
23. Riddle, R. D.; Johnson, R. L.; Laufer, E., Tabin, C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 1993, 75 (7), 1401-1416.
24. Chang, D. T.; Lopez, A.; von Kessler, D. P.; Chiang, C.; Simandl, B. K.; Zhao, R.; Seldin, M. F.; Fallon, J. F., Beachy, P. A. Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development 1994, 120 (11), 3339-3353.
25. Echelard, Y.; Epstein, D. J.; St-Jacques, B.; Shen, L.; Mohler, J.; McMahon, J. A., McMahon, A. P. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 1993, 75 (7), 1417-1430.
26. Kyttala, M.; Tallila, J.; Salonen, R.; Kopra, O.; Kohlschmidt, N.; Paavola-Sakki, P.; Peltonen, L., Kestila, M. MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome. Nat. Genet. 2006, 38 (2), 155-157.
27. Pan, J.; Wang, Q., Snell, W. J. Cilium-generated signaling and cilia-related disorders. Lab Invest. 2005, 85 (4), 452-463.
28. Bezard, E.; Baufreton, J.; Owens, G.; Crossman, A. R.; Dudek, H.; Taupignon, A., Brotchie, J. M. Sonic hedgehog is a neuromodulator in the adult subthalamic nucleus. FASEB J. 2003, 17 (15), 2337-2338.
29. Calcutt, N. A.; Allendoerfer, K. L.; Mizisin, A. P.; Middlemas, A.; Freshwater, J. D.; Burgers, M.; Ranciato, R.; Delcroix, J. D.; Taylor, F. R.; Shapiro, R.; Strauch, K.; Dudek, H.; Engber, T. M.; Galdes, A.; Rubin, L. L., Tomlinson, D. R. Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy. J. Clin. Invest. 2003, 111 (4), 507-514.
30. Aszterbaum, M.; Rothman, A.; Johnson, R. L.; Fisher, M.; Xie, J.; Bonifas, J. M.; Zhang, X.; Scott, M. P., Epstein, E. H., Jr. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J. Invest. Dermatol. 1998, 110 (6), 885-888.
31. Hahn, H.; Christiansen, J.; Wicking, C.; Zaphiropoulos, P. G.; Chidambaram, A.; Gerrard, B.; Vorechovsky, I.; Bale, A. E.; Toftgard, R.; Dean, M., Wainwright, B. A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities. J. Biol. Chem. 1996, 271 (21), 12125-12128.
32. Hahn, H.; Wicking, C.; Zaphiropoulous, P. G.; Gailani, M. R.; Shanley, S.; Chidambaram, A.; Vorechovsky, I.; Holmberg, E.; Unden, A. B.; Gillies, S.; Negus, K.; Smyth, I.; Pressman, C.; Leffell, D. J.; Gerrard, B.; Goldstein, A. M.; Dean, M.; Toftgard, R.; Chenevix-Trench, G.; Wainwright, B., Bale, A. E. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996, 85 (6), 841-851.
33. Johnson, R. L.; Rothman, A. L.; Xie, J.; Goodrich, L. V.; Bare, J. W.; Bonifas, J. M.; Quinn, A. G.; Myers, R. M.; Cox, D. R.; Epstein, E. H., Jr., Scott, M. P. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996, 272 (5268), 1668-1671.
34. Makino, S.; Masuya, H.; Ishijima, J.; Yada, Y., Shiroishi, T. A spontaneous mouse mutation, mesenchymal dysplasia (mes), is caused by a deletion of the most C-terminal cytoplasmic domain of patched (ptc). Dev. Biol. 2001, 239 (1), 95-106.
35. Marini, K. D.; Payne, B. J.; Watkins, D. N., Martelotto, L. G. Mechanisms of Hedgehog signalling in cancer. Growth Factors 2011, 29 (6), 221-234.
36. Pietsch, T.; Waha, A.; Koch, A.; Kraus, J.; Albrecht, S.; Tonn, J.; Sorensen, N.; Berthold, F.; Henk, B.; Schmandt, N.; Wolf, H. K.; von Deimling, A.; Wainwright, B.; Chenevix-Trench, G.; Wiestler, O. D., Wicking, C. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res. 1997, 57 (11), 2085-2088.
37. Raffel, C.; Jenkins, R. B.; Frederick, L.; Hebrink, D.; Alderete, B.; Fults, D. W., James, C. D. Sporadic medulloblastomas contain PTCH mutations. Cancer Res. 1997, 57 (5), 842-845.
38. Wang, W.; Wang, J.; Li, J.; Mao, L.; Guo, F., Zhang, B. New mutation of the patched homologue 1 gene in a Chinese family with naevoid basal cell carcinoma syndrome. Br. J. Oral Maxillofac. Surg. 2009, 47 (5), 366-369.
39. Xie, J.; Johnson, R. L.; Zhang, X.; Bare, J. W.; Waldman, F. M.; Cogen, P. H.; Menon, A. G.; Warren, R. S.; Chen, L. C.; Scott, M. P., Epstein, E. H., Jr. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res. 1997, 57 (12), 2369-2372.
40. 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 (21), 2743-2748.
41. Frank-Kamenetsky, M.; Zhang, X. M.; Bottega, S.; Guicherit, O.; Wichterle, H.; Dudek, H.; Bumcrot, D.; Wang, F. Y.; Jones, S.; Shulok, J.; Rubin, L. L., Porter, J. A. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists type=journal> and antagonists. J. Biol. 2002, 1 (2), 10.
42. King, R. W. Roughing up Smoothened: chemical modulators of hedgehog signaling. J. Biol. 2002, 1 (2), 8.
43. Chen, J. K.; Taipale, J.; Young, K. E.; Maiti, T., Beachy, P. A. Small molecule modulation of Smoothened activity. Proc. Natl. Acad. Sci. U S A. 2002, 99 (22), 14071-14076.
44. Stanton, B. Z., Peng, L. F. Small-molecule modulators of the Sonic Hedgehog signaling pathway. Mol. Biosyst. 2010, 6 (1), 44-54.
45. 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 (3), 200-213.
46. Tremblay, M. R.; Lescarbeau, A.; Grogan, M. J.; Tan, E.; Lin, G.; Austad, B. C.; Yu, L. C.; Behnke, M. L.; Nair, S. J.; Hagel, M.; White, K.; Conley, J.; Manna, J. D.; Alvarez-Diez, T. M.; Hoyt, J.; Woodward, C. N.; Sydor, J. R.; Pink, M.; MacDougall, J.; Campbell, M. J.; Cushing, J.; Ferguson, J.; Curtis, M. S.; McGovern, K.; Read, M. A.; Palombella, V. J.; Adams, J., Castro, A. C. Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). J. Med. Chem. 2009, 52 (14), 4400-4418.
47. Tzelepi, V.; Karlou, M.; Wen, S.; Hoang, A.; Logothetis, C.; Troncoso, P., Efstathiou, E. Expression of hedgehog pathway components in prostate carcinoma microenvironment: shifting the balance towards autocrine signalling. Histopathology 2011, 58 (7), 1037-1047.
48. Singh, S.; Wang, Z.; Liang Fei, D.; lack, K. E.; Goetz, J. A.; Tokhunts, R.; Giambelli, C.; Rodriguez-Blanco, J.; Long, J.; Lee, E.; Briegel, K. J.; Bejarano, P. A.; Dmitrovsky, E.; Capobianco, A. J., Robbins, D. J. Hedgehog-producing cancer cells respond to and require autocrine Hedgehog activity. Cancer Res. 2011, 71 (13), 4454-4463.
49. Varas, A.; Hernandez-Lopez, C.; Valencia, J.; Mattavelli, S.; Martinez, V. G.; Hidalgo, L.; Gutierrez-Frias, C.; Zapata, A. G.; Sacedon, R., Vicente, A. Survival and function of human thymic dendritic cells are dependent on autocrine Hedgehog signaling. J. Leukoc. Biol. 2008, 83 (6), 1476-1483.
50. Atkinson, P. J.; Dellovade, T.; Albers, D.; Von Schack, D.; Saraf, K.; Needle, E.; Reinhart, P. H., Hirst, W. D. Sonic Hedgehog signaling in astrocytes is dependent on p38 mitogen-activated protein kinase and G-protein receptor kinase 2. J. Neurochem. 2009, 108 (6), 1539-1549.
51. Ruiz i Altaba, A.; Nguyen, V., Palma, V. The emergent design of the neural tube: prepattern, SHH morphogen and GLI code. Curr. Opin. Genet. Dev. 2003, 13 (5), 513-521.
52. Devine, C. A.; Sbrogna, J. L.; Guner, B.; Osgood, M.; Shen, M.C., Karlstrom, R. O. A dynamic Gli code interprets Hh signals to regulate induction, patterning, and endocrine cell specification in the zebrafish pituitary. Dev. Biol. 2009, 326 (1), 143-154.
53. Ruiz Altaba, A.; Mas, C., Stecca, B. The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol. 2007. 17 (9), 438-447.
54. Stecca, B., Ruiz, I. A. A. Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals. J. Mol. Cell Biol. 2010, 2 (2), 84-95.
55. Chan, I. S.; Guy, C. D.; Chen, Y.; Lu, J.; Swiderska-Syn, M.; Michelotti, G. A.; Karaca, G.; Xie, G.; Kruger, L.; Syn, W. K.; Anderson, B. R.; Pereira, T. A.; Choi, S. S.; Baldwin, A. S. Diehl, A. M. Paracrine hedgehog signaling drives metabolic changes in hepatocellular carcinoma. Cancer Res. 2012, 72 (24), 6344-6350.
56. Shaw, A.; Gipp, J., Bushman, W. The Sonic Hedgehog pathway stimulates prostate tumor growth by paracrine signaling and recapitulates embryonic gene expression in tumor myofibroblasts. Oncogene 2009, 28 (50), 4480-4490.
57. Visbal, A. P.; LaMarca, H. L.; Villanueva, H.; Toneff, M. J.; Li, Y.; Rosen, J. M., Lewis, M. T. Altered differentiation and paracrine stimulation of mammary epithelial cell proliferation by conditionally activated Smoothened. Dev. Biol. 2011, 352 (1), 116-127.
58. Theunissen, J. W., de Sauvage, F. J. Paracrine Hedgehog signaling in cancer. Cancer Res. 2009, 69 (15), 6007-6010.
59. Kar, S.; Deb, M.; Sengupta, D.; Shilpi, A.; Bhutia, S. K., Patra, S. K. Intricacies of hedgehog signaling pathways: a perspective in tumorigenesis. Exp. Cell Res. 2012, 318 (16), 1959-1972.
60. Zhou, X.; Liu, Z.; Jang, F.; Xiang, C.; Li, Y., He, Y. Autocrine Sonic hedgehog attenuates inflammation in cerulein-induced acute pancreatitis in mice via upregulation of IL-10. PLoS One. 2012, 7 (8), e44121.
61. Zurawel, R. H.; Allen, C.; Chiappa, S.; Cato, W.; Biegel, J.; Cogen, P.; de Sauvage, F., Raffel, C. Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma. Genes Chromosomes Cancer 2000, 27 (1), 44-51.
62. Lam, C. W.; Xie, J.; To, K. F.; Ng, H. K.; Lee, K. C.; Yuen, N. W.; Lim, P. L.; Chan, L. Y.; Tong, S. F., McCormick, F. A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene 1999, 18 (3), 833-836.
63. Seto, M.; Ohta, M.; Asaoka, Y.; Ikenoue, T.; Tada, M.; Miyabayashi, K.; Mohri, D.; Tanaka, Y.; Ijichi, H.; Tateishi, K.; Kanai, F.; Kawabe, T., Omata, M. Regulation of the hedgehog signaling by the mitogen-activated protein kinase cascade in gastric cancer. Mol. Carcinog. 2009, 48 (8), 703-712.
64. Levina, E.; Chen, M.; Carkner, R.; Shtutman, M., Buttyan, R. Paracrine Hedgehog increases the steroidogenic potential of prostate stromal cells in a Gli-dependent manner. Prostate 2012, 72 (8), 817-824.
65. Kolterud, A.; Grosse, A. S.; Zacharias, W. J.; Walton, K. D.; Kretovich, K. E.; Madison, B. B.; Waghray, M.; Ferris, J. E.; Hu, C.; Merchant, J. L.; Dlugosz, A. A.; Kottmann, A. H., Gumucio, D. L. Paracrine Hedgehog signaling in stomach and intestine: new roles for hedgehog in gastrointestinal patterning. Gastroenterology 2009, 137 (2), 618-628.
66. 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 (7211), 406-410.
67. Zunich, S. M.; Douglas, T.; Valdovinos, M.; Chang, T.; Bushman, W.; Walterhouse, D.; Iannaccone, P., Lamm, M. L. Paracrine sonic hedgehog signalling by prostate cancer cells induces osteoblast differentiation. Mol. Cancer. 2009, 8, 12.
68. Endo, H.; Utani, A.; Matsumoto, F.; Kuroki, T.; Yoshimoto, S.; Ichinose, M., Shinkai, H. A possible paracrine hedgehog signalling pathway in neurofibromas from patients with neurofibromatosis type 1. Br. J. Dermatol. 2003, 148 (2), 337-341.
69. Bailey, J. M.; Mohr, A. M., Hollingsworth, M. A. Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene 2009, 28 (40), 3513-3525.
70. Lauth, M., Toftgard, R. Non-canonical activation of GLI transcription factors: implications for targeted anti-cancer therapy. Cell Cycle 2007, 6 (20), 2458-2463.
71. Blotta, S.; Jakubikova, J.; Calimeri, T.; Roccaro, A. M.; Amodio, N.; Azab, A. K.; Foresta, U.; Mitsiades, C. S.; Rossi, M.; Todoerti, K.; Molica, S.; Morabito, F.; Neri, A.; Tagliaferri, P.; Tassone, P.; Anderson, K. C., Munshi, N. C. Canonical and non canonical Hedgehog pathway in the pathogenesis of multiple myeloma. Blood, 2012.
72. Stecca, B.; Mas, C.; Clement, V.; Zbinden, M.; Correa, R.; Piguet, V.; Beermann, F., Ruiz, I. A. A. Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc. Natl. Acad. Sci. U S A. 2007, 104 (14), 5895-5900.
73. 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. U S A. 2008, 105 (12), 4838-4843.
74. Ho, L., Alman, B. Protecting the hedgerow: p53 and hedgehog pathway interactions. Cell Cycle 2010, 9 (3), 506-511.
75. Malek, R.; Matta, J.; Taylor, N.; Perry, M. E., Mendrysa, S. M. The p53 inhibitor MDM2 facilitates Sonic Hedgehog-mediated tumorigenesis and influences cerebellar foliation. PLoS One 2011, 6 (3), e17884.
76. Mohan, A. L.; Friedman, M. D.; Ormond, D. R.; Tobias, M.; Murali, R., Jhanwar-Uniyal, M. PI3K/mTOR signaling pathways in medulloblastoma. Anticancer Res. 2012, 32 (8), 3141-3146.
77. Elia, D.; Madhala, D.; Ardon, E.; Reshef, R., Halevy, O. Sonic hedgehog promotes proliferation and differentiation of adult muscle cells: Involvement of MAPK/ERK and PI3K/Akt pathways. Biochim. Biophys. Acta. 2007, 1773 (9), 1438-1446.
78. Ramaswamy, B.; Lu, Y.; Teng, K. Y.; Nuovo, G.; Li, X.; Shapiro, C. L., Majumder, S. Hedgehog signaling is a novel therapeutic target in tamoxifen-resistant breast cancer aberrantly activated by PI3K/AKT pathway. Cancer Res. 2012, 72 (19), 5048-5059.
79. Yoo, Y. A.; Kang, M. H.; Lee, H. J.; Kim, B. H.; Park, J. K.; Kim, H. K.; Kim, J. S., Oh, S. C. Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer. Cancer Res. 2011, 71 (22), 7061-7070.
80. Wei, L., Xu, Z. Cross-signaling among phosphinositide-3 kinase, mitogen-activated protein kinase and sonic hedgehog pathways exists in esophageal cancer. Int. J. Cancer. 2011, 129 (2), 275-284.
81. Katoh, Y., Katoh, M. Integrative genomic analyses on GLI1: positive regulation of GLI1 by Hedgehog-GLI, TGFbeta-Smads, and RTK-PI3K-AKT signals, and negative regulation of GLI1 by Notch-CSL-HES/HEY, and GPCR-Gs-PKA signals. Int. J. Oncol. 2009, 35 (1), 187-192.
82. Ju, B.; Spitsbergen, J.; Eden, C. J.; Taylor, M. R., Chen, W. Co-activation of hedgehog and AKT pathways promote tumorigenesis in zebrafish. Mol. Cancer 2009, 8, 40.
83. Riobo, N. A.; Lu, K.; Ai, X.; Haines, G. M., Emerson, C. P., Jr. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc. Natl. Acad. Sci. USA 2006, 103 (12), 4505-4510.
84. Wang, Y.; Ding, Q.; Yen, C. J.; Xia, W.; Izzo, J. G.; Lang, J. Y.; Li, C. W.; Hsu, J. L.; Miller, S. A.; Wang, X.; Lee, D. F.; Hsu, J. M.; Huo, L.; Labaff, A. M.; Liu, D.; Huang, T. H.; Lai, C. C.; Tsai, F. J.; Chang, W. C.; Chen, C. H.; Wu, T. T.; Buttar, N. S.; Wang, K. K.; Wu, Y.; Wang, H.; Ajani, J., Hung, M. C. The crosstalk of mTOR/S6K1 and Hedgehog pathways. Cancer Cell 2012, 21 (3), 374-387.
85. Lu, J. T.; Zhao, W. D.; He, W., Wei, W. Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway. Acta. Pharmacol. Sin. 2012, 33 (5), 691-700.
86. Chang, S. L.; Harshman, L. C., Presti, J. C., Jr. Impact of common medications on serum total prostate-specific antigen levels: analysis of the National Health and Nutrition Examination Survey. J. Clin. Oncol. 2010, 28 (25), 3951-3957.
87. Schnidar, H.; Eberl, M.; Klingler, S.; Mangelberger, D.; Kasper, M.; Hauser-Kronberger, C.; Regl, G.; Kroismayr, R.; Moriggl, R.; Sibilia, M., Epidermal growth factor receptor signaling synergizes with Hedgehog/GLI in oncogenic transformation via activation of the MEK/ERK/JUN pathway. Cancer Res. 2009, 69 (4), 1284-1292.
88. Lai, L. P.; DaSilva, K. A., Mitchell, J. Regulation of Indian hedgehog mRNA levels in chondrocytic cells by ERK1/2 and p38 mitogen-activated protein kinases. J. Cell Physiol. 2005, 203 (1), 177-185.
89. Kessaris, N.; Jamen, F.; Rubin, L. L., Richardson, W. D. Cooperation between sonic hedgehog and fibroblast growth factor/MAPK signalling pathways in neocortical precursors. Development. 2004, 131 (6), 1289-1298.
90. Katoh, M. Networking of WNT, FGF, Notch, BMP, and Hedgehog signaling pathways during carcinogenesis. Stem Cell Rev. 2007, 3 (1), 30-38.
91. Morris, J. P. T.; Wang, S. C. Hebrok, M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer. 2010. 10 (10), 683-695.
92. Roma, J.; Almazan-Moga, A.; Sanchez de Toledo, J., Gallego, S. Notch, wnt, and hedgehog pathways in rhabdomyosarcoma: from single pathways to an integrated network. Sarcoma 2012, 2012, 695603.
93. Yanai, K.; Nakamura, M.; Akiyoshi, T.; Nagai, S.; Wada, J.; Koga, K.; Noshiro, H.; Nagai, E.; Tsuneyoshi, M.; Tanaka, M., Katano, M. Crosstalk of hedgehog and Wnt pathways in gastric cancer. Cancer Lett. 2008, 263 (1), 145-156.
94. Zardawi, S. J.; O'Toole, S. A.; Sutherland, R. L., Musgrove, E. A. type=contributor>Dysregulation of Hedgehog, Wnt and Notch signalling pathways in breast cancer. Histol Histopathol. 2009, 24 (3), 385-398.
95. Javelaud, D.; Pierrat, M. J., Mauviel, A. Crosstalk between TGF-beta and hedgehog signaling in cancer. FEBS Lett. 2012, 586 (14), 2016-2025.
96. Yoo, Y. A.; Kang, M. H.; Kim, J. S., Oh, S. C. Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Carcinogenesis 2008, 29 (3), 480-490.
97. Johnson, R. W.; Nguyen, M. P.; Padalecki, S. S.; Grubbs, B. G.; Merkel, A. R.; Oyajobi, B. O.; Matrisian, L. M.; Mundy, G. R., Sterling, J. A. TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling. Cancer Res. 2011, 71 (3), 822-831.
98. Maitah, M. Y.; Ali, S.; Ahmad, A.; Gadgeel, S., Sarkar, F. H. Up-regulation of sonic hedgehog contributes to TGF-beta1-induced epithelial to mesenchymal transition in NSCLC cells. PLoS One 2011, 6 (1), e16068.
99. Bell, R. M. A review of complementary and alternative medicine practices among cancer survivors. Clin. J. Oncol. Nurs. 2010, 14 (3), 365-370.
100. Go, V. L.; Wong, D. A.; Resnick, M. S., Heber, D. Evaluation of botanicals and dietary supplements therapy in cancer patients. J Nutr. 2001. 131 (1), 179S-180S.
101. Michaud, L. B.; Karpinski, J. P.; Jones, K. L., Espirito, J. Dietary supplements in patients with cancer: risks and key concepts, part 2. Am. J. Health Syst. Pharm. 2007, 64 (5), 467-480.
102. Michaud, L. B.; Karpinski, J. P.; Jones, K. L., Espirito, J. Dietary supplements in patients with cancer: risks and key concepts, part 1. Am. J. Health Syst. Pharm. 2007, 64 (4), 369-381.
103. Varker, K. A.; Ansel, A.; Aukerman, G., Carson, W. E., Review of complementary and alternative medicine and selected nutraceuticals: background for a pilot study on nutrigenomic intervention in patients with advanced cancer. Altern. Ther. Health Med. 2012, 18 (2), 26-34.
104. Jia, L. Cancer complementary and alternative medicine research at the US national cancer institute. Chin. J. Integr. Med. 2012, 18 (5), 325-332.
105. Smith, W. B., White, J. D. Complementary and alternative medicine in cancer: a National Cancer Institute perspective. Expert Opin. Biol. Ther. 2001, 1 (3), 339-341.
106. Richardson, M. A.; Sanders, T.; Palmer, J. L.; Greisinger, A., Singletary, S. E. Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology. J. Clin. Oncol. 2000, 18 (13), 2505-2514.
107. Labbozzetta, M.; Baruchello, R.; Marchetti, P.; Gueli, M. C.; Poma, P.; Notarbartolo, M.; Simoni, D., D'Alessandro, N. Lack of nucleophilic addition in the isoxazole and pyrazole iketone modified analogs of curcumin; implications for their antitumor and chemosensitizing activities. Chem. Biol. Interact. 2009, 181 (1), 29-36.
108. Sreekanth, C. N.; Bava, S. V.; Sreekumar, E., Anto, R. J. Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer. Oncogene 2011, 30 (28), 3139-3152.
109. Gurley, B. J. Pharmacokinetic Herb-Drug Interactions (Part 1): Origins, Mechanisms, and the Impact of Botanical Dietary Supplements. Planta Med. 2012, 78 (13), 1478-1489.
110. Gurley, B. J.; Fifer, E. K., Gardner, Z. Pharmacokinetic Herb-Drug Interactions (Part 2): Drug Interactions Involving Popular Botanical Dietary Supplements and Their Clinical Relevance. Planta Med. 2012, 78 (13), 1490-1514.
111. Bailey, D. G.; Dresser, G., Arnold, J. M. Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? CMAJ. 2013, 185 (4), 309-316.
112. Keeler, R. F., Binns, W. Teratogenic compounds of Veratrum californicum (Durand). I. Preparation and characterization of fractions and alkaloids for biologic testing. Can. J. Biochem. 1966, 44 (6), 819-828.
113. 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 (6), 829-838.
114. 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 (1), 5-10.
115. Keeler, R. F. Teratogenic compounds in Veratrum californicum (Durand) IX. Structure-activity relation. Teratology 1970, 3 (2), 169-173.
116. Chiang, C.; Litingtung, Y.; Lee, E.; Young, K. E.; Corden, J. L.; Westphal, H., Beachy, P. A. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 1996, 383 (6599), 407-413.
117. Cooper, M. K.; Porter, J. A.; Young, K. E., Beachy, P. A. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 1998, 280 (5369), 1603-1607.
118. Gorlin, R. J., Goltz, R. W. Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A syndrome. N. Engl. J. Med. 1960, 262, 908-912.
119. Wicking, C.; Gillies, S.; Smyth, I.; Shanley, S.; Fowles, L.; Ratcliffe, J.; Wainwright, B., Chenevix-Trench, G. De novo mutations of the Patched gene in nevoid basal cell carcinoma syndrome help to define the clinical phenotype. Am. J. Med. Genet. 1997, 73 (3), 304-307.
120. 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 (7009), 707-712.
121. Feldmann, G.; Habbe, N.; Dhara, S.; Bisht, S.; Alvarez, H.; Fendrich, V.; Beaty, R.; Mullendore, M.; Karikari, C.; Bardeesy, N.; Oullette, M. M.; Yu, W., Maitra, A. Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut 2008, 57 (10), 1420-1430.
122. 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 (5586), 1559-1561.
123. Watkins, D. N.; Berman, D. M.; Burkholder, S. G.; Wang, B.; Beachy, P. A., Baylin, S. B. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 2003, 422 (6929), 313-317.
124. Romer, J. T.; Kimura, H.; Magdaleno, S.; Sasai, K.; Fuller, C.; Baines, H.; Connelly, M.; Stewart, C. F.; Gould, S.; Rubin, L. L. Curran, T. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice. Cancer Cell 2004, 6 (3), 229-240.
125. Miller-Moslin, K.; Peukert, S.; Jain, R. K.; McEwan, M. A.; Karki, R.; Llamas, L.; Yusuff, N.; He, F.; Li, Y.; Sun, Y.; Dai, M.; Perez, L.; Michael, W.; Sheng, T.; Lei, H.; Zhang, R.; Williams, J.; Bourret, A.; Ramamurthy, A.; Yuan, J.; Guo, R.; Matsumoto, M.; Vattay, A.; Maniara, W.; Amaral, A.; Dorsch, M., Kelleher, J. F., 1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity. J. Med. Chem. 2009, 52 (13), 3954-3968.
126. Robarge, K. D.; Brunton, S. A.; Castanedo, G. M.; Cui, Y.; Dina, M. S.; Goldsmith, R.; Gould, S. E.; Guichert, O.; Gunzner, J. L.; Halladay, J.; Jia, W.; Khojasteh, C.; Koehler, M. F.; Kotkow, K.; La, H.; Lalonde, R. L.; Lau, K.; Lee, L.; Marshall, D.; Marsters, J.C., Jr.; Murray, L. J.; Qian, C.; Rubin, L. L.; Salphati, L.; Stanley, M. S.; Stibbard, J. H.; Sutherlin, D. P.; Ubhayaker, S.; Wang, S.; Wong, S., Xie, M. GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorg. Med. Chem. Lett. 2009, 19 (19), 5576-5581.
127. Esatbeyoglu, T.; Huebbe, P.; Ernst, I. M.; Chin, D.; Wagner, A.E., Rimbach, G. Curcumin-from molecule to biological function. Angew Chem Int Ed Engl. 2012. 51 (22), 5308-5332.
128. Ye, M. X.; Li, Y.; Yin, H., Zhang, J. Curcumin: updated molecular mechanisms and intervention targets in human lung cancer. Int. J. Mol Sci. 2012, 13 (3), 3959-3978.
129. Ji, J. L.; Huang, X. F., Zhu, H. L. Curcumin and its formulations: potential anti-cancer agents. Anticancer Agents Med. Chem. 2012, 12 (3), 210-218.
130. Hossain, D. M.; Bhattacharyya, S.; Das, T., Sa, G. Curcumin: the multi-targeted therapy for cancer regression. Front Biosci. (Schol Ed). 2012, 4, 335-355.
131. Gao, W.; Chan, J. Y.; ei, W. I., Wong, T. S. Anti-Cancer Effects of Curcumin On Head And Neck Cancers. Anticancer Agents Med. Chem. 2012, 12(9), 1110-1116.
132. Darvesh, A. S.; Aggarwal, B. B., Bishayee, A. Curcumin and liver cancer: a review. Curr. Pharm. Biotechnol. 2012, 13 (1), 218-228.
133. Oyagbemi, A. A.; Saba, A. B., Ibraheem, A. O. Curcumin: from food spice to cancer prevention. Asian Pac. J. Cancer Prev. 2009, 10 (6), 963-967.
134. Zhou, Q. M.; Wang, X. F.; Liu, X. J.; Zhang, H.; Lu, Y. Y.; Huang, S., Su, S. B. Curcumin improves MMC-based chemotherapy by simultaneously sensitising cancer cells to MMC and reducing MMC-associated side-effects. Eur. J. Cancer. 2011, 47 (14), 2240-2247.
135. Shafaee, Z.; Schmidt, H.; Du, W.; Posner, M., Weichselbaum, R. type=contributor>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 (6), 765-770.
136. Fajardo, A. M.; MacKenzie, D. A.; Ji, M.; Deck, L. M.; Vander Jagt, D. L.; Thompson, T. A., Bisoffi, M. The curcumin analog ca27 down-regulates androgen receptor through an oxidative stress mediated mechanism in human prostate cancer cells. Prostate 2012, 72 (6), 612-625.
137. Choi, H. Y.; Lim, J. E., Hong, J. H. Curcumin interrupts the interaction between the androgen receptor and Wnt/beta-catenin signaling pathway in LNCaP prostate cancer cells. Prostate Cancer Prostatic Dis. 2010, 13 (4), 343-349.
138. Shi, Q.; Shih, C. C., Lee, K. H. Novel anti-prostate cancer curcumin analogues that enhance androgen receptor degradation activity. Anticancer Agents Med. Chem. 2009, 9 (8), 904-912.
139. Mimeault, M., Batra, S. K. Potential applications of curcumin and its novel synthetic analogs and nanotechnology-based formulations in cancer prevention and therapy. Chin. Med. 2011, 6, 31.
140. Slusarz, A.; Shenouda, N. S.; Sakla, M. S.; Drenkhahn, S. K.; Narula, A. S.; MacDonald, R. S.; Besch-Williford, C. L., Lubahn, D. B. Common botanical compounds inhibit the hedgehog signaling pathway in prostate cancer. Cancer Res. 2010, 70 (8), 3382-3390.
141. Yallapu, M. M.; Dobberpuhl, M. R.; Maher, D. M.; Jaggi, M. Chauhan, S. C. Design of curcumin loaded cellulose nanoparticles for prostate cancer. Curr. Drug Metab. 2012, 13 (1), 120-128.
142. Yallapu, M. M.; Jaggi, M., Chauhan, S. C. Poly (beta-cyclodextrin)/curcumin self-assembly: a novel approach to improve curcumin delivery and its therapeutic efficacy in prostate cancer cells. Macromol. Biosci. 2010, 10 (10), 1141-1151.
143. Valentini, A.; Conforti, F.; Crispini, A.; De Martino, A.; Condello, R.; Stellitano, C.; Rotilio, G.; Ghedini, M.; Federici, G.; Bernardini, S., Pucci, D. Synthesis, oxidant properties, and antitumoral effects of a heteroleptic palladium(II) complex of curcumin on human prostate cancer cells. J. Med. Chem. 2009, 52 (2), 484-491.
144. Elamin, M. H.; Shinwari, Z.; Hendrayani, S. F.; Al-Hindi, H.; Al-Shail, E.; Khafaga, Y.; Al-Kofide, A., Aboussekhra, A. Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells. Mol. Carcinog. 2010, 49 (3), 302-314.
145. Lim, K. J.; Bisht, S.; Bar, E. E.; Maitra, A., Eberhart, C. G. A polymeric nanoparticle formulation of curcumin inhibits growth, clonogenicity and stem-like fraction in malignant brain tumors. Cancer Biol Ther. 2011. 11 (5), 464-473.
146. McCleary-Wheeler, A. L.; McWilliams, R., Fernandez-Zapico, M. E. Aberrant signaling pathways in pancreatic cancer: a two compartment view. Mol Carcinog. 2012. 51 (1), 25-39.
147. Bisht, S.; Brossart, P.; Maitra, A., Feldmann, G. Agents targeting the Hedgehog pathway for pancreatic cancer treatment. Curr. Opin. Investig. Drugs. 2010, 11 (12), 1387-1398.
148. Johnson, J., de Mejia, E. G. Dietary factors and pancreatic cancer: the role of food bioactive compounds. Mol. Nutr. Food Res. 2011, 55 (1), 58-73.
149. Bao, B.; Ali, S.; Banerjee, S.; Wang, Z.; Logna, F.; Azmi, A. S.; Kong, D.; Ahmad, A.; Li, Y.; Padhye, S., Sarkar, F. H. Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res. 2012, 72 (1), 335-345.
150. Jee, S. H.; Shen, S. C.; Tseng, C. R.; Chiu, H. C., Kuo, M. L. Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells. J. Invest. Dermatol. 1998, 111 (4), 656-661.
151. Jian, L. Soy, isoflavones, and prostate cancer. Mol. Nutr. Food Res. 2009, 53 (2), 217-226.
152. Steiner, C.; Arnould, S.; Scalbert, A., Manach, C. Isoflavones and the prevention of breast and prostate cancer: new perspectives opened by nutrigenomics. Br. J. Nutr. 2008, 99 (E Suppl 1), ES78-ES108.
153. Iwasaki, M.; Inoue, M.; Otani, T.; Sasazuki, S.; Kurahashi, N.; Miura, T.; Yamamoto, S., Tsugane, S. Plasma isoflavone level and subsequent risk of breast cancer among Japanese women: a nested case-control study from the Japan Public Health Center-based prospective study group. J. Clin. Oncol. 2008, 26 (10), 1677-1683.
154. Kurahashi, N.; Iwasaki, M.; Sasazuki, S.; Otani, T.; Inoue, M., Tsugane, S. Soy product and isoflavone consumption in relation to prostate cancer in Japanese men. Cancer Epidemiol Biomarkers Prev. 2007, 16 (3), 538-545.
155. Day, J. K.; Bauer, A. M.; DesBordes, C.; Zhuang, Y.; Kim, B. E.; Newton, L. G.; Nehra, V.; Forsee, K. M.; MacDonald, R. S.; Besch-Williford, C.; Huang, T. H., Lubahn, D. B. Genistein alters methylation patterns in mice. J. Nutr. 2002, 132 (8 Suppl), 2419S-2423S.
156. Day, J. K.; Besch-Williford, C.; McMann, T. R.; Hufford, M. G.; Lubahn, D. B., MacDonald, R. S. Dietary genistein increased DMBA-induced mammary adenocarcinoma in wild-type, but not ER alpha KO, mice. Nutr. Cancer. 2001, 39 (2), 226-232.
157. Sakla, M. S.; Shenouda, N. S.; Ansell, P. J.; Macdonald, R. S., Lubahn, D. B. Genistein affects HER2 protein concentration, activation, and promoter regulation in BT-474 human breast cancer cells. Endocrine 2007, 32 (1), 69-78.
158. Perabo, F. G.; Von Low, E. C.; Ellinger, J.; von Rucker, A.; Muller, S. C., Bastian, P. J. Soy isoflavone genistein in prevention and treatment of prostate cancer. Prostate Cancer Prostatic Dis. 2008, 11 (1), 6-12.
159. Sarkar, F. H., Li, Y. Soy isoflavones and cancer prevention. Cancer Invest. 2003, 21 (5), 744-757.
160. Zhang, L.; Li, L.; Jiao, M.; Wu, D.; Wu, K.; Li, X.; Zhu, G.; Yang, L.; Wang, X.; Hsieh, J. T., He, D. Genistein inhibits the stemness properties of prostate cancer cells through targeting Hedgehog-Gli1 pathway. Cancer Lett. 2012, 323 (1):48-57.
161. Jang, M.; Cai, L.; Udeani, G. O.; Slowing, K. V.; Thomas, C. F.; Beecher, C. W.; Fong, H. H.; Farnsworth, N. R.; Kinghorn, A. D.; Mehta, R. G.; Moon, R. C., Pezzuto, J. M. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997, 275 (5297), 218-220.
162. Aggarwal, B. B.; Bhardwaj, A.; Aggarwal, R. S.; Seeram, N. P.; Shishodia, S., Takada, Y. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 2004, 24 (5A), 2783-2840.
163. Baxter, R. A. Anti-aging properties of resveratrol: review and report of a potent new antioxidant skin care formulation. J. Cosmet. Dermatol. 2008, 7 (1), 2-7.
164. Wu, J. M.; Hsieh, T. C., Wang, Z. Cardioprotection by resveratrol: a review of effects/targets in cultured cells and animal tissues. Am. J. Cardiovasc. Dis. 2011, 1 (1), 38-47.
165. Smoliga, J. M.; Baur, J. A., Hausenblas, H. A. Resveratrol and health--a comprehensive review of human clinical trials. Mol. Nutr. Food Res. 2011, 55 (8), 1129-1141.
166. Guerrero, R. F.; Garcia-Parrilla, M. C.; Puertas, B., Cantos-Villar, E. Wine, resveratrol and health: a review. Nat. Prod. Commun. 2009, 4 (5), 635-658.
167. Nakata, R.; Takahashi, S., Inoue, H. Recent advances in the study on resveratrol. Biol. Pharm. Bull. 2012, 35 (3), 273-279.
168. Scott, E.; Steward, W. P.; Gescher, A. J., Brown, K. Resveratrol in human cancer chemoprevention--choosing the 'right' dose. Mol. Nutr. Food Res. 2012, 56 (1), 7-13.
169. Dierks, C.; Beigi, R.; Guo, G. R.; Zirlik, K.; Stegert, M. R.; Manley, P.; Trussell, C.; Schmitt-Graeff, A.; Landwerlin, K.; Veelken, H., Warmuth, M. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 2008, 14 (3), 238-249.
170. Zhao, C.; Chen, A.; Jamieson, C. H.; Fereshteh, M.; Abrahamsson, A.; Blum, J.; Kwon, H. Y.; Kim, J.; Chute, J. P.; Rizzieri, D.; Munchhof, M.; VanArsdale, T.; Beachy, P. A., Reya, T. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009, 458 (7239), 776-779.
171. Liao, H. F.; Su, Y. C.; Zheng, Z. Y.; Jhih Cai, C.; Hou, M. H.; Chao, K. S., Chen, Y. J. Sonic hedgehog signaling regulates Bcr-Abl expression in human chronic myeloid leukemia cells. Biomed. Pharmacother. 2012, 66 (5), 378-383.
172. Puissant, A.; Grosso, S.; Jacquel, A.; Belhacene, N.; Colosetti, P.; Cassuto, J. P., Auberger, P. Imatinib mesylate-resistant human chronic myelogenous leukemia cell lines exhibit high sensitivity to the phytoalexin resveratrol. FASEB J. 2008, 22 (6), 1894-1904.
173. Mo, W.; Xu, X.; Xu, L.; Wang, F.; Ke, A.; Wang, X., Guo, C. Resveratrol inhibits proliferation and induces apoptosis through the hedgehog signaling pathway in pancreatic cancer cell. Pancreatology 2011, 11 (6), 601-609.
174. Zhuang, L.; Lin, J.; Lu, M. L.; Solomon, K. R., Freeman, M. R. Cholesterol-rich lipid rafts mediate akt-regulated survival in prostate cancer cells. Cancer Res. 2002, 62 (8), 2227-2231.
175. Fujiki, H. Green tea: Health benefits as cancer preventive for humans. Chem. Rec. 2005, 5 (3), 119-132.
176. Pastore, R. L., Fratellone, P. Potential health benefits of green tea (Camellia sinensis): a narrative review. Explore (NY). 2006, 2 (6), 531-539.
177. Schneider, C., Segre, T. Green tea: potential health benefits. Am Fam. Physician. 2009, 79 (7), 591-594.
178. Serafini, M.; Del Rio, D.; Yao, D. N.; Bettuzzi, S., Peluso, I. Health Benefits of Tea. In: SourceHerbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. Boca Raton (FL). Benzie I. F. F., Wachtel-Galor, S. Ed.; CRC Press; 2011.
179. Madhala-Levy, D.; Williams, V. C.; Hughes, S. M.; Reshef, R., Halevy, O. Cooperation between Shh and IGF-I in promoting myogenic proliferation and differentiation via the MAPK/ERK and PI3K/Akt pathways requires Smo activity. J. Cell Physiol. 2012, 227 (4), 1455-1464.
180. Kim, J.; Aftab, B. T.; Tang, J. Y.; Kim, D.; Lee, A. H.; Rezaee, M.; Kim, J.; Chen, B.; King, E. M.; Borodovsky, A.; Riggins, G. J.; Epstein, E. H., Jr.; Beachy, P. A., Rudin, C. M. Itraconazole and Arsenic Trioxide Inhibit Hedgehog Pathway Activation and Tumor Growth Associated with Acquired Resistance to Smoothened Antagonists. Cancer Cell 2013, 23 (1), 23-34.
181. Tang, G. Q.; Yan, T. Q.; Guo, W.; Ren, T. T.; Peng, C. L.; Zhao, H.; Lu, X. C.; Zhao, F. L., Han, X. Epigallocatechin-3-gallate induces apoptosis and suppresses proliferation by inhibiting the human Indian Hedgehog pathway in human chondrosarcoma cells. J. Cancer Res. Clin. Oncol. 2010, 136 (8), 1179-1185.
182. Tang, S. N.; Fu, J.; Nall, D.; Rodova, M.; Shankar, S., Srivastava, R. K. Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics. Int. J. Cancer. 2012, 131 (1), 30-40.
183. Tang, S. N.; Singh, C.; Nall, D.; Meeker, D.; Shankar, S., Srivastava, R. K. The dietary bioflavonoid quercetin synergizes with epigallocathechin gallate (EGCG) to inhibit prostate cancer stem cell characteristics, invasion, migration and epithelial-mesenchymal transition. J. Mol. Signal. 2010, 5, 14.
184. Wang, Y.; Li, M.; Xu, X.; Song, M.; Tao, H., Bai, Y. Green tea epigallocatechin-3-gallate (EGCG) promotes neural progenitor cell proliferation and sonic hedgehog pathway activation during adult hippocampal neurogenesis. Mol. Nutr. Food Res. 2012, 56 (8), 1292-1303.
185. Favaro, R.; Valotta, M.; Ferri, A. L.; Latorre, E.; Mariani, J.; Giachino, C.; Lancini, C.; Tosetti, V.; Ottolenghi, S.; Taylor, V., Nicolis, S. K. Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nat. Neurosci. 2009, 12 (10), 1248-1256.
186. Sugawara, T.; Jadhav, V.; Ayer, R., Zhang, J. Simvastatin attenuates cerebral vasospasm and improves outcomes by upregulation of PI3K/Akt pathway in a rat model of subarachnoid hemorrhage. Acta. Neurochir. Suppl. 2008, 102, 391-394.
187. Pozniak, C. D., Pleasure, S. J. A tale of two signals: Wnt and Hedgehog in dentate neurogenesis. Sci. STKE. 2006, 2006 (319), pe5.
188. Arai, M. A.; Tateno, C.; Hosoya, T.; Koyano, T.; Kowithayakorn, T. Ishibashi, M. Hedgehog/GLI-mediated transcriptional inhibitors from Zizyphus cambodiana. Bioorg. Med. Chem. 2008, 16 (21), 9420-9424.
189. Hosoya, T.; Arai, M. A.; Koyano, T.; Kowithayakorn, T., Ishibashi, M. Naturally occurring small-molecule inhibitors of hedgehog/ GLI-mediated transcription. Chembiochem. 2008, 9 (7), 1082-1092.
190. Rifai, Y.; Arai, M. A.; Koyano, T.; Kowithayakorn, T., Ishibashi, M. Terpenoids and a flavonoid glycoside from Acacia pennata leaves as hedgehog/GLI-mediated transcriptional inhibitors. J. Nat. Prod. 2010, 73 (5), 995-997.
191. Arai, M. A.; Tateno, C.; Koyano, T.; Kowithayakorn, T.; Kawabe, S., Ishibashi, M. New hedgehog/GLI-signaling inhibitors from Adenium obesum. Org. Biomol. Chem. 2011, 9 (4), 1133-1139.
192. Rifai, Y.; Arai, M. A.; Koyano, T.; Kowithayakorn, T., Ishibashi, M. Acoschimperoside P, 2'-acetate: a Hedgehog signaling inhibitory constituent from Vallaris glabra. J. Nat. Med. 2011, 65 (3-4), 629-632.
193. Rifai, Y.; Arai, M. A.; Sadhu, S. K.; Ahmed, F., Ishibashi, M. New Hedgehog/GLI signaling inhibitors from Excoecaria agallocha. Bioorg. Med. Chem. Lett. 2011, 21 (2), 718-722.
194. Eichenmuller, M.; Hemmerlein, B.; von Schweinitz, D., Kappler, R. Betulinic acid induces apoptosis and inhibits hedgehog signalling in rhabdomyosarcoma. Br. J. Cancer 2010, 103 (1), 43-51.
195. Keeler, R. F. Teratogenic compounds of Veratrum californicum (Durand) X. Cyclopia in rabbits produced by cyclopamine. Teratology 1970, 3 (2), 175-180.
196. Ferruzzi, P.; Mennillo, F.; De Rosa, A.; Giordano, C.; Rossi, M.; Benedetti, G.; Magrini, R.; Pericot Mohr, G.; Miragliotta, V.; Magnoni, L.; Mori, E.; Thomas, R.; Tunici, P., Bakker, A. In vitro and in vivo characterization of a novel Hedgehog signaling antagonist in human glioblastoma cell lines. Int. J. Cancer 2012, 131 (2), E33-E44.
197. Metcalfe, C., de Sauvage, F. J. Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists. Cancer Res. 2011, 71 (15), 5057-5061.