Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Identification of Natural Compounds to Inhibit Sonic Hedgehog Pathway in Oral Cancer

Author(s): Hitarth Patel, Jigna Joshi, Apexa Raval and Franky Shah*

Volume 22, Issue 5, 2022

Published on: 08 July, 2021

Page: [905 - 913] Pages: 9

DOI: 10.2174/1871520621666210708100747

Price: $65


Background: Conventional treatment resistance remains a significant problem in cancer care. Cancer stem cells might play a major role in treatment resistance, and as a result, basic stem cell pathways are instrumental in cancer. Sonic Hedgehog signaling has not been widely studied in oral cancer, and being one of the major cancer stem cell pathways, targeting it with natural compounds could open many opportunities in the treatment scenario.

Objective: The objective of the study was to identify the role of various natural compounds as an anti-cancer agent for oral cancer by targeting the Hedgehog signaling pathway.

Methods: The selection of natural compounds were identified through literature review and NPACT database. The protein (3M1N and 3MXW) and ligand molecules were retrieved through the PDB and PubChem database. To carry out docking experiments, the AutoDock 4.2 program was used to study the interaction between the identified protein and ligand.

Results: Among the 13 identified natural compounds, the top three were selected based on their binding energy. The higher the binding energy on the negative side, the better the interaction formed between protein and ligand. The natural compound showing best results with 3M1N protein were Butein, Biochanin-A, and Curcumin, whereas, with 3MXW, Zerumbone, Curcumin, and Butein were identified.

Conclusion: The identified natural compounds have shown better binding energy to bind the Hh ligands in the absence/ presence of a known Sonic Hedgehog inhibitor. Based on the results, natural compounds can be utilized in the current treatment modality for oral cancer either as an individual anti-cancer agent or in combination with the known Sonic Hedgehog inhibitor to curb the increasing incidence rate. Yet, in-vitro evidence in lab setup is required.

Keywords: Cancer stem cells, oral cancer, sonic hedgehog, molecular docking, natural compounds, signaling pathway.

Graphical Abstract
Ferlay, J.; Colombet, M.; Soerjomataram, I.; Mathers, C.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer, 2019, 144(8), 1941-1953.
[] [PMID: 30350310]
Gonnissen, A.; Isebaert, S.; Haustermans, K. Targeting the Hedgehog signaling pathway in cancer: Beyond smoothened. Oncotarget, 2015, 6(16), 13899-13913.
[] [PMID: 26053182]
Pietrobono, S.; Gagliardi, S.; Stecca, B. Non-canonical Hedgehog signaling pathway in cancer: Activation of GLI transcription factors beyond smoothened. Front. Genet., 2019, 10, 556.
[] [PMID: 31244888]
Skoda, A.M.; Simovic, D.; Karin, V.; Kardum, V.; Vranic, S.; Serman, L. The role of the Hedgehog signaling pathway in cancer: A comprehensive review. Bosn. J. Basic Med. Sci., 2018, 18(1), 8-20.
[] [PMID: 29274272]
Patel, H.; Joshi, J.; Desai, U.; Raval, A.; Shah, F. Hedgehog signaling: An emerging targeting therapy in cancer. Asian J. Pharm. Pharmacol., 2018, 4(5), 535-545.
Yang, L.; Xie, G.; Fan, Q.; Xie, J. Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene, 2010, 29(4), 469-481.
[] [PMID: 19935712]
Rimkus, T.K.; Carpenter, R.L.; Qasem, S.; Chan, M.; Lo, H.W. Targeting the sonic hedgehog signaling pathway: Review of smoothened and GLI inhibitors. Cancers (Basel), 2016, 8(2)E22
[] [PMID: 26891329]
Fan, H.; Oro, A.E.; Scott, M.P.; Khavari, P.A. Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog. Nat. Med., 1997, 3(7), 788-792.
[] [PMID: 9212109]
Oro, A.E.; Higgins, K.M.; Hu, Z.; Bonifas, J.M.; Epstein, E.H., Jr; Scott, M.P. Basal cell carcinomas in mice overexpressing sonic hedgehog. Science, 1997, 276(5313), 817-821.
[] [PMID: 9115210]
Gupta, S.; Takebe, N.; Lorusso, P. Targeting the Hedgehog pathway in cancer. Ther. Adv. Med. Oncol., 2010, 2(4), 237-250.
[] [PMID: 21789137]
Cousins, F.L.; Farley, J.K.; Kerrigan, R.; Mukherjee, S.; Darzi, S.; Gargett, C.E.; Deane, J.A. The effects of hedgehog ligand neutralising antibody 5E1 in a mouse model of endometriosis. BMC Res. Notes, 2020, 13(1), 454.
[] [PMID: 32977859]
Parascandolo, A.; Laukkanen, M.O.; De Rosa, N.; Ugolini, C.; Cantisani, M.C.; Cirafici, A.M.; Basolo, F.; Santoro, M.; Castellone, M.D. A dual mechanism of activation of the Sonic Hedgehog pathway in anaplastic thyroid cancer: Crosstalk with RAS-BRAF-MEK pathway and ligand secretion by tumor stroma. Oncotarget, 2017, 9(4), 4496-4510.
[] [PMID: 29435119]
Zhang, Q.Y.; Wang, F.X.; Jia, K.K.; Kong, L.D. Natural product interventions for chemotherapy and radiotherapy-induced side effects. Front. Pharmacol., 2018, 9, 1253.
[] [PMID: 30459615]
Sanders, K.; Moran, Z.; Shi, Z.; Paul, R.; Greenlee, H. Natural products for cancer prevention: Clinical update 2016. Semin. Oncol. Nurs., 2016, 32(3), 215-240.
[] [PMID: 27539278]
Gullett, N.P.; Ruhul Amin, A.R.M.; Bayraktar, S.; Pezzuto, J.M.; Shin, D.M.; Khuri, F.R.; Aggarwal, B.B.; Surh, Y.J.; Kucuk, O. Cancer prevention with natural compounds. Semin. Oncol., 2010, 37(3), 258-281.
[] [PMID: 20709209]
Hong, W.K.; Sporn, M.B. Recent advances in chemoprevention of cancer. Science, 1997, 278(5340), 1073-1077.
[] [PMID: 9353183]
Mangal, M.; Sagar, P.; Singh, H.; Raghava, G.P.S.; Agarwal, S.M. NPACT: Naturally occurring plant-based anti-cancer compound-activity-target database. Nucleic Acids Res., 2013, 41(Database issue), D1124-D1129.
[] [PMID: 23203877]
Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem 2019 update: Improved access to chemical data. Nucleic Acids Res., 2019, 47(D1), D1102-D1109.
[] [PMID: 30371825]
Burley, S.K.; Berman, H.M.; Bhikadiya, C.; Bi, C.; Chen, L.; Di Costanzo, L.; Christie, C.; Dalenberg, K.; Duarte, J.M.; Dutta, S.; Feng, Z.; Ghosh, S.; Goodsell, D.S.; Green, R.K.; Guranović, V.; Guzenko, D.; Hudson, B.P.; Kalro, T.; Liang, Y.; Lowe, R.; Namkoong, H.; Peisach, E.; Periskova, I.; Prlić, A.; Randle, C.; Rose, A.; Rose, P.; Sala, R.; Sekharan, M.; Shao, C.; Tan, L.; Tao, Y.P.; Valasatava, Y.; Voigt, M.; Westbrook, J.; Woo, J.; Yang, H.; Young, J.; Zhuravleva, M.; Zardecki, C. RCSB Protein Data Bank: Biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy. Nucleic Acids Res., 2019, 47(D1), D464-D474.
[] [PMID: 30357411]
Pepinsky, R.B.; Rayhorn, P.; Day, E.S.; Dergay, A.; Williams, K.P.; Galdes, A.; Taylor, F.R.; Boriack-Sjodin, P.A.; Garber, E.A. Mapping sonic hedgehog-receptor interactions by steric interference. J. Biol. Chem., 2000, 275(15), 10995-11001.
[] [PMID: 10753901]
Maun, H.R.; Wen, X.; Lingel, A.; de Sauvage, F.J.; Lazarus, R.A.; Scales, S.J.; Hymowitz, S.G. Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active site. J. Biol. Chem., 2010, 285(34), 26570-26580.
[] [PMID: 20504762]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[] [PMID: 15264254]
Wang, J.; Wang, W.; Kollman, P.A.; Case, D.A. Automatic atom type and bond type perception in molecular mechanical calculations. J. Mol. Graph. Model., 2006, 25(2), 247-260.
[] [PMID: 16458552]
Brenke, R.; Kozakov, D.; Chuang, G.Y.; Beglov, D.; Hall, D.; Landon, M.R.; Mattos, C.; Vajda, S. Fragment-based identification of druggable ‘hot spots’ of proteins using Fourier domain correlation techniques. Bioinformatics, 2009, 25(5), 621-627.
[] [PMID: 19176554]
Kozakov, D.; Grove, L.E.; Hall, D.R.; Bohnuud, T.; Mottarella, S.; Luo, L.; Xia, B.; Beglov, D.; Vajda, S. The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins. Nat. Protoc., 2016, 10(5), 733-755.
[ ]
Ngan, C.H.; Hall, D.R.; Zerbe, B.; Grove, L.E.; Kozakov, D.; Vajda, S. FTSite: High accuracy detection of ligand binding sites on unbound protein structures. Bioinformatics, 2012, 28(2), 286-287.
[] [PMID: 22113084]
Morris, G.M.; Goodsell, D.S.; Pique, M.E.; Lindstrom, W.; Lindy Huey, R.; Forli, S.; Hart, W.E.; Halliday, S.; Belew, R.; Olson, A.J. Autodock4 and AutoDockTools4: Automated docking with selective receptor flexiblity. J. Comput. Chem., 2009, 30(16), 2785-2791.
Pandya, N.; Archana, M.; Rakesh, R.; Kumar, P. Screening of diverse phytochemicals with aurora kinase C protein: An in silico approach. J. Drug Deliv. Therapeut., 2019, 9, 67-74.
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[] [PMID: 33538338]
Thavarool, S.B.; Muttath, G.; Nayanar, S.; Duraisamy, K.; Bhat, P.; Shringarpure, K.; Nayak, P.; Tripathy, J.P.; Thaddeus, A.; Philip, S.; Satheesan, B. Improved survival among oral cancer patients: Findings from a retrospective study at a tertiary care cancer centre in rural Kerala, India. World J. Surg. Oncol., 2019, 17(1), 15.
[] [PMID: 30635062]
Pignon, J.P.; le Maître, A.; Maillard, E.; Bourhis, J. Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother. Oncol., 2009, 92(1), 4-14.
[] [PMID: 19446902]
Carneiro-Neto, J.N.; de-Menezes, J.D.S.; Moura, L.B.; Massucato, E.M.S.; de-Andrade, C.R. Protocols for management of oral complications of chemotherapy and/or radiotherapy for oral cancer: Systematic review and meta-analysis current. Med. Oral Patol. Oral Cir. Bucal, 2017, 22(1), e15-e23.
[] [PMID: 27918734]
Salmaso, V.; Moro, S. Bridging molecular docking to molecular dynamics in exploring ligand-protein recognition process: An Overview. Front. Pharmacol., 2018, 9, 923.
[] [PMID: 30186166]
Takabatake, K.; Shimo, T.; Murakami, J.; Anqi, C.; Kawai, H.; Yoshida, S.; Wathone Oo, M.; Haruka, O.; Sukegawa, S.; Tsujigiwa, H.; Nakano, K.; Nagatsuka, H. The role of sonic hedgehog signaling in the tumor microenvironment of oral squamous cell carcinoma. Int. J. Mol. Sci., 2019, 20(22)E5779
[] [PMID: 31744214]
Srinath, S.; Iyengar, A.R.; Mysorekar, V. Sonic hedgehog in oral squamous cell carcinoma: An immunohistochemical study. J. Oral Maxillofac. Pathol., 2016, 20(3), 377-383.
[] [PMID: 27721600]
Fan, H.X.; Wang, S.; Zhao, H.; Liu, N.; Chen, D.; Sun, M.; Zheng, J.H. Sonic hedgehog signaling may promote invasion and metastasis of oral squamous cell carcinoma by activating MMP-9 and E-cadherin expression. Med. Oncol., 2014, 31(7), 41.
[] [PMID: 24915900]
Devassy, J.G.; Nwachukwu, I.D.; Jones, P.J.H. Curcumin and cancer: Barriers to obtaining a health claim. Nutr. Rev., 2015, 73(3), 155-165.
[] [PMID: 26024538]
Shindikar, A.; Singh, A.; Nobre, M.; Kirolikar, S. Curcumin and resveratrol as promising natural remedies with nanomedicine approach for the effective treatment of triple negative breast cancer. J. Oncol., 2016, 20169750785
[] [PMID: 27242900]
Huang, Y.C.; Chao, K.S.C.; Liao, H.F.; Chen, Y.J. Targeting sonic hedgehog signaling by compounds and derivatives from natural products. Evid. Based Complement. Alternat. Med., 2013, 2013748587
[] [PMID: 23762158]
Mirzaei, H.; Masoudifar, A.; Sahebkar, A.; Zare, N.; Nahand, J.S.; Rashidi, B.; Mehrabian, E.; Mohammadi, M.; Mirzaei, H.R.; Jaafari, M.R. MicroRNA: A novel target of curcumin in cancer therapy. J. Cell. Physiol., 2018, 233(4), 3004-3015.
[] [PMID: 28617957]
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.
[] [PMID: 20025076]
Bao, C.; Kramata, P.; Lee, H.J.; Suh, N. Regulation of Hedgehog signaling in cancer by natural and dietary compounds. Mol. Nutr. Food Res., 2018, 62(1)
[] [PMID: 29164817]
Sun, X.D.; Liu, X.E.; Huang, D.S. Curcumin reverses the epithelial-mesenchymal transition of pancreatic cancer cells by inhibiting the Hedgehog signaling pathway. Oncol. Rep., 2013, 29(6), 2401-2407.
[] [PMID: 23563640]
Meng, X.; Cai, J.; Liu, J.; Han, B.; Gao, F.; Gao, W.; Zhang, Y.; Zhang, J.; Zhao, Z.; Jiang, C. Curcumin increases efficiency of γ-irradiation in gliomas by inhibiting Hedgehog signaling pathway. Cell Cycle, 2017, 16(12), 1181-1192.
[] [PMID: 28463091]
Zhu, J.Y.; Yang, X.; Chen, Y.; Jiang, Y.; Wang, S.J.; Li, Y.; Wang, X.Q.; Meng, Y.; Zhu, M.M.; Ma, X.; Huang, C.; Wu, R.; Xie, C.F.; Li, X.T.; Geng, S.S.; Wu, J.S.; Zhong, C.Y.; Han, H.Y. Curcumin suppresses lung cancer stem cells via inhibiting Wnt/β-catenin and Sonic Hedgehog pathways. Phytother. Res., 2017, 31(4), 680-688.
[] [PMID: 28198062]
Li, X.; Wang, X.; Xie, C.; Zhu, J.; Meng, Y.; Chen, Y.; Li, Y.; Jiang, Y.; Yang, X.; Wang, S.; Chen, J.; Zhang, Q.; Geng, S.; Wu, J.; Zhong, C.; Zhao, Y. Sonic hedgehog and Wnt/β-catenin pathways mediate curcumin inhibition of breast cancer stem cells. Anticancer Drugs, 2018, 29(3), 208-215.
[] [PMID: 29356693]
Wang, D.; Kong, X.; Li, Y.; Qian, W.; Ma, J.; Wang, D.; Yu, D.; Zhong, C. Curcumin inhibits bladder cancer stem cells by suppressing Sonic Hedgehog pathway. Biochem. Biophys. Res. Commun., 2017, 493(1), 521-527.
[] [PMID: 28870814]
Li, Y.; Zhang, T. Targeting cancer stem cells by curcumin and clinical applications. Cancer Lett., 2014, 346(2), 197-205.
[] [PMID: 24463298]
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.
[] [PMID: 21193839]
Jung, C.H.; Kim, J.H.; Hong, M.H.; Seog, H.M.; Oh, S.H.; Lee, P.J.; Kim, G.J.; Kim, H.M.; Um, J.Y.; Ko, S.G. Phenolic-rich fraction from Rhus verniciflua Stokes (RVS) suppress inflammatory response via NF-kappaB and JNK pathway in lipopolysaccharide-induced RAW 264.7 macrophages. J. Ethnopharmacol., 2007, 110(3), 490-497.
[] [PMID: 17112694]
Bordoloi, D.; Monisha, J.; Roy, N.K.; Padmavathi, G.; Banik, K.; Harsha, C.; Wang, H.; Kumar, A.P.; Arfuso, F.; Kunnumakkara, A.B. An investigation on the therapeutic potential of Butein, A tretrahydroxychalcone against human oral squamous cell carcinoma. Asian Pac. J. Cancer Prev., 2019, 20(11), 3437-3446.
[] [PMID: 31759370]
Yu, C.; Zhang, P.; Lou, L.; Wang, Y. Perspectives regarding the role of Biochanin A in humans. Front. Pharmacol., 2019, 10, 793.
[] [PMID: 31354500]
Ren, G.; Shi, Z.; Teng, C.; Yao, Y. Antiproliferative activity of combined Biochanin A and ginsenoside Rh2 on MDA-MB-231 and MCF-7 human breast cancer cells. Molecules, 2018, 23(11)E2908
[] [PMID: 30413008]
Zhang, F.F.; Haslam, D.E.; Terry, M.B.; Knight, J.A.; Andrulis, I.L.; Daly, M.B.; Buys, S.S.; John, E.M. Dietary isoflavone intake and all-cause mortality in breast cancer survivors: The breast cancer family registry. Cancer, 2017, 123(11), 2070-2079.
[] [PMID: 28263368]
Perez-Cornago, A.; Appleby, P.N.; Boeing, H.; Gil, L.; Kyrø, C.; Ricceri, F.; Murphy, N.; Trichopoulou, A.; Tsilidis, K.K.; Khaw, K.T.; Luben, R.N.; Gislefoss, R.E.; Langseth, H.; Drake, I.; Sonestedt, E.; Wallström, P.; Stattin, P.; Johansson, A.; Landberg, R.; Nilsson, L.M.; Ozasa, K.; Tamakoshi, A.; Mikami, K.; Kubo, T.; Sawada, N.; Tsugane, S.; Key, T.J.; Allen, N.E.; Travis, R.C. Circulating isoflavone and lignan concentrations and prostate cancer risk: a meta-analysis of individual participant data from seven prospective studies including 2,828 cases and 5,593 controls. Int. J. Cancer, 2018, 143(11), 2677-2686.
[] [PMID: 29971774]
You, J.; Sun, Y.; Bo, Y.; Zhu, Y.; Duan, D.; Cui, H.; Lu, Q. The association between dietary isoflavones intake and gastric cancer risk: a meta-analysis of epidemiological studies. BMC Public Health, 2018, 18(1), 510.
[] [PMID: 29665798]
Haque, M.A.; Jantan, I.; Arshad, L.; Bukhari, S.N.A. Exploring the immunomodulatory and anticancer properties of zerumbone. Food Funct., 2017, 8(10), 3410-3431.
[] [PMID: 28714500]
Sung, B.; Jhurani, S.; Ahn, K.S.; Mastuo, Y.; Yi, T.; Guha, S.; Liu, M.; Aggarwal, B.B. Zerumbone down-regulates chemokine receptor CXCR4 expression leading to inhibition of CXCL12-induced invasion of breast and pancreatic tumor cells. Cancer Res., 2008, 68(21), 8938-8944.
[] [PMID: 18974138]
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.
[] [PMID: 18357592]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy