Updated Monday, September 25, 2017
 Journal Tools
RSS Feed
Sample Copy
Submit a Manuscript
Contact Us
Thanking Peer Reviewers
 Language Polishing
Journal of Chinese Integrative Medicine: Volume 10, 2012   Issue 3,  Pages: 256-263

DOI: 10.3736/jcim20120303
Review Article
Advances in Smoothened-targeting therapies for pancreatic cancer: implication for drug discovery from herbal medicines
1. Jin-bin Han (Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China )
2. Yong-qiang Hua (Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China )
3. Lian-yu Chen (Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China )
4. Lu-ming Liu (Department of Integrative Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China E-mail: llm1010@163.com)
ABSTRACT: Smoothened (SMO) is a member of sonic hedgehog homology (SHH) signaling pathway. It plays a key role as a bridge between patched-1 (PTCH-1) and Gli. Aberrant SHH expression can be detected in various malignant tissues, and the expression in pancreatic cancer stem cells is higher apparently. SHH signals are closely associated with self-duplication of cancer stem cells, formation of tumor vessels as well as matrixes. SMO antagonists such as cyclopamine, GDC-0449 and so on show potential to inhibit activity of SHH signaling, and arrest the growth as well as metastases of tumors. Recently, a few of SMO antagonists have been studied in phase Ⅰ clinical trials and some are in phase Ⅱ, meanwhile, phase Ⅰ or Ⅱ trials of SMO antagonists to treat pancreatic cancer are performed currently. As the classical SMO antagonist, cyclopamine is extracted from a medicinal plant. Perhaps researchers may be able to determine more effective SMO-targeting drugs from herbal medicines in the future.
Welcome to JIM! You are the number 10029 reader of this article!
Download Article:
[Full Text]      [PDF]      [Previous]      [Next]      [This Issue]
Please cite this article as:
Han JB, Hua YQ, Chen LY, Liu LM. Advances in Smoothened-targeting therapies for pancreatic cancer: implication for drug discovery from herbal medicines. J Chin Integr Med / Zhong Xi Yi Jie He Xue Bao. 2012; 10(3): 256-263.
1Simeone DM. Pancreatic cancer stem cells: implications for the treatment of pancreatic cancer[J].Clin Cancer Res, 2008, 14(18): 5646-5648.  
2Burke R, Nellen D, Bellotto M, Hafen E, Senti KA, Dickson BJ, Basler K. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells[J].Cell, 1999, 99(7): 803-815.  
3Taipale J, Cooper MK, Maiti T, Beachy PA. Patched acts catalytically to suppress the activity of Smoothened[J].Nature, 2002, 418(6900): 892-897.  
4Tenzen T, Allen BL, Cole F, Kang JS, Krauss RS, McMahon AP. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice[J].Dev Cell, 2006, 10(5): 647-656.  
5Stecca B, Ruiz I Altaba A. Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals[J].J Mol Cell Biol, 2010, 2(2): 84-95.  
6Ruiz I Altaba A. Catching a Gli-mpse of Hedgehog[J].Cell, 1997, 90(2): 193-196.  
7Price MA, Kalderon D. Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by glycogen synthase kinase 3 and vasein kinase 1[J].Cell, 2002, 108(6): 823-835.  
8Cheng SY, Bishop JM. Suppressor of fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex[J].Proc Natl Acad Sci U S A, 2002, 99(8): 5442-5447.  
9Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G, Wainwright B, Bale AE. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome[J].Cell, 1996, 85(6): 841-851.  
10Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH Jr, de Sauvage FJ. Activating Smoothened mutations in sporadic basal-cell carcinoma[J].Nature, 1998, 391(6662): 90-92.  
11Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D. Mutations in SUFU predispose to medulloblastoma[J].Nat Genet, 2002, 31(3): 306-310.  
12Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernndez-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw AL, Hebrok M. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis[J].Nature, 2003, 425(6960): 851-856.  
13Jia J, Tong C, Jiang J. Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its C-terminal tail[J].Genes Dev, 2003, 17(21): 2709-2720.  
14May SR, Ashique AM, Karlen M, Wang B, Shen Y, Zarbalis K, Reiter J, Ericson J, Peterson AS. Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli[J].Dev Biol, 2005, 287(2): 378-389.  
15Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y, Wright CV, Hebrok M, Lewis BC. Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci U S A. 2007; 104(12): 5103-5108
16Kawahira H, Scheel DW, Smith SB, German MS, Hebrok M. Hedgehog signaling regulates expansion of pancreatic epithelial cells[J].Dev Biol, 2005, 280(1): 111-121.  
17Kayed H, Kleeff J, Osman T, Keleg S, Büchler MW, Friess H. Hedgehog signaling in the normal and diseased pancreas[J].Pancreas, 2006, 32(2): 119-129.  
18Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses[J].Science, 2008, 321(5897): 1801-1806.  
19Feldmann 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[J].Gut, 2008, 57(10): 1420-1430.  
20Feldmann G, Fendrich V, McGovern K, Bedja D, Bisht S, Alvarez H, Koorstra JB, Habbe N, Karikari C, Mullendore M, Gabrielson KL, Sharma R, Matsui W, Maitra A. An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer[J].Mol Cancer Ther, 2008, 7(9): 2725-2735.  
21Ohuchida K, Mizumoto K, Fujita H, Yamaguchi H, Konomi H, Nagai E, Yamaguchi K, Tsuneyoshi M, Tanaka M. Sonic hedgehog is an early developmental marker of intraductal papillary mucinous neoplasms: clinical implications of mRNA levels in pancreatic juice[J].J Pathol, 2006, 210(1): 42-48.  
22Tian H, Callahan CA, DuPree KJ, Darbonne WC, Ahn CP, Scales SJ, de Sauvage FJ. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis[J].Proc Natl Acad Sci U S A, 2009, 106(11): 4254-4259.  
23Asai J, Takenaka H, Kusano KF, Ii M, Luedemann C, Curry C, Eaton E, Iwakura A, Tsutsumi Y, Hamada H, Kishimoto S, Thorne T, Kishore R, Losordo DW. Topical sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling[J].Circulation, 2006, 113(20): 2413-2424.  
24Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer[J].Science, 2009, 324(5933): 1457-1461.  
25Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, Marshall D, Fu L, Januario T, Kallop D, Nannini-Pepe M, Kotkow K, Marsters JC, Rubin LL, de Sauvage FJ. A paracrine requirement for hedgehog signalling in cancer[J].Nature, 2008, 455(7211): 406-410.  
26Bailey JM, Swanson BJ, Hamada T, Eggers JP, Singh PK, Caffery T, Ouellette MM, Hollingsworth MA. Sonic hedgehog promotes desmoplasia in pancreatic cancer[J].Clin Cancer Res, 2008, 14(19): 5995-6004.  
27Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz I Altaba A. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity[J].Curr Biol, 2007, 17(2): 165-172.  
28Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells[J].Cancer Res, 2006, 66(12): 6063-6071.  
29Peacock 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 signaling maintains a tumor stem cell compartment in multiple myeloma[J].Proc Natl Acad Sci U S A, 2007, 104(10): 4048-4053.  
30Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM. Identification of pancreatic cancer stem cells[J].Cancer Res, 2007, 67(3): 1030-1037.  
31Nakamura K, Sasajima J, Mizukami Y, Sugiyama Y, Yamazaki M, Fujii R, Kawamoto T, Koizumi K, Sato K, Fujiya M, Sasaki K, Tanno S, Okumura T, Shimizu N, Kawabe J, Karasaki H, Kono T, Ii M, Bardeesy N, Chung DC, Kohgo Y. Hedgehog promotes neovascularization in pancreatic cancers by regulating Ang-1 and IGF-1 expression in bone-marrow derived pro-angiogenic cells[J].PLoS One, 2010, 5(1): e8824.  
32Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened[J].Genes Dev, 2002, 16(21): 2743-2748.  
33Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, Karikari C, Alvarez H, Iacobuzio-Donahue C, Jimeno A, Gabrielson KL, Matsui W, Maitra A. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers[J].Cancer Res, 2007, 67(5): 2187-2196.  
34Lee SW, Moskowitz MA, Sims JR. Sonic hedgehog inversely regulates the expression of angiopoietin-1 and angiopoietin-2 in fibroblasts[J].Int J Mol Med, 2007, 19(3): 445-451.  
35Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration[J].Nat Med, 2003, 9(6): 702-712.  
36Evangelista M, Tian H, de Sauvage FJ. The hedgehog signaling pathway in cancer[J].Clin Cancer Res, 2006, 12(20 Pt 1): 5924-5928.  
37Yamazaki 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, Fujiya M, Ashida T, Chung DC, Kohgo Y. Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells[J].Cancer Sci, 2008, 99(6): 1131-1138.  
38Kim SK, Melton DA. Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor[J].Proc Natl Acad Sci U S A, 1998, 95(22): 13036-13041.  
39Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN, Beachy PA. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours[J].Nature, 2003, 425(6960): 846-851.  
40Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T, Pujara K, Stinson J, Callahan CA, Tang T, Bazan JF, Kan Z, Seshagiri S, Hann CL, Gould SE, Low JA, Rudin CM, de Sauvage FJ. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma[J].Science, 2009, 326(5952): 572-574.  
41Dijkgraaf GJ, Alicke B, Weinmann L, Januario T, West K, Modrusan Z, Burdick D, Goldsmith R, Robarge K, Sutherlin D, Scales SJ, Gould SE, Yauch RL, de Sauvage FJ. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance[J].Cancer Res, 2010, 71(2): 435-444.  
42LoRusso PM, Rudin CM, Reddy JC, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Chang I, Darbonne WC, Graham RA, Zerivitz KL, Low JA, Von Hoff DD. Phase Ⅰ trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors[J].Clin Cancer Res, 2011, 17(8): 2502-2511.  
43LoRusso PM, Rudin CM, Borad MJ, Vernillet L, Darbonne WC, Mackey H, DiMartino JF, de Sauvage F, Low JA, Von Hoff DD. A first-in-human, first-in-class, phase (ph) I study of systemic Hedgehog (Hh) pathway antagonist, GDC-0449, in patients (pts) with advanced solid tumors[J].J Clin Oncol (Meeting Abstracts), 2008, 26(15 Suppl): 3516.  
44Berlin J, et al. A phase 2, randomized, double-blind, placebo-controlled study of hedgehog pathway inhibitor (HPI) GDC-0449 in patients with previously untreated metastatic colorectal cancer (mCRC). Presented at 35th European Society for Medical Oncology ESMO Congress October 8, 2010, Milan Italy (Vol. 21 Suppl 8, p. Abstract LBA21). [2011-08-15]. http://www.mendeley.com/research/phase-2-randomized-doubleblind-placebocontrolled-study-hedgehog-pathway-inhibitor-hpi-gdc0449-patients-previously-untreated-metastatic-colorectal-cancer-mcrc/.
45Merchant AA, Matsui W. Targeting Hedgehog — a cancer stem cell pathway[J].Clin Cancer Res, 2010, 16(12): 3130-3140.  
46Kelleher FC. Hedgehog signaling and therapeutics in pancreatic cancer[J].Carcinogenesis, 2010, 32(4): 445-451.  
47Ailles L, Siu LL. Targeting the Hedgehog pathway in cancer: can the spines be smoothened? Clin Cancer Res. 2011; 17(8): 2071-2073.
48Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee YC, Peaceman D, Ozdemirli M, Rodriguez O, Macdonald TJ, Albanese C, Toretsky JA, Uren A. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway[J].J Clin Invest, 2011, 121(1): 148-160.  
49Mazumdar T, Devecchio J, Agyeman A, Shi T, Houghton JA. Blocking Hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells[J].Cancer Res, 2011, 71(17): 5904-5914.  
 Home | Current Issue | Past Issues | SearchRSS
Copyright © 2013-2018 by JIM Editorial Office. All rights reserved. ISSN 2095-4964; CN 31-2083/R. 沪ICP备110264号