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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

General Research Article

The Efficient Activity of Glabridin and its Derivatives Against EGFRmediated Inhibition of Breast Cancer

Author(s): Arabinda Ghosh*, Debanjana Ghosh, Nobendu Mukerjee, Swastika Maitra, Padmashree Das, Abhijit Dey, Souty M.Z. Sharkawi, Georgios D. Zouganelis, Athanasios Alexiou, Somdatta Yashwant Chaudhari, Ritika Sharma, Sonali Arun Waghmare, Marios Papadakis* and Gaber El-Saber Batiha

Volume 31, Issue 5, 2024

Published on: 07 July, 2023

Page: [573 - 594] Pages: 22

DOI: 10.2174/0929867330666230303120942

Price: $65


Background: Breast cancer (BC) is one of the most typical causes of cancer death in women worldwide. Activated epidermal growth factor receptor (EGFR) signaling has been increasingly associated with BC development and resistance to cytotoxic drugs. Due to its significant association with tumour metastasis and poor prognosis, EGFR-mediated signaling has emerged as an attractive therapeutic target in BC. Mainly in all BC cases, mutant cells over-expresses EGFR. Certain synthetic drugs are already used to inhibit the EGFR-mediated pathway to cease metastasis, with several phytocompounds also revealing great chemopreventive activities.

Methods: This study used chemo-informatics to predict an effective drug from some selected phytocompounds. The synthetic drugs and the organic compounds were individually screened for their binding affinities, with EGFR being the target protein using molecular docking techniques.

Results: The binding energies were compared to those of synthetic drugs. Among phytocompounds, Glabridin (phytocompound of Glycyrrhiza glabra) manifested the best dock value of -7.63 Kcal/mol, comparable to that of the highly effective anti-cancer drug Afatinib. The glabridin derivatives also exhibited comparable dock values.

Conclusion: The AMES properties deciphered the non-toxic features of the predicted compound. Pharmacophore modeling and in silico cytotoxicity predictions also exhibited a superior result assuring their drug likeliness. Therefore, Glabridin can be conceived as a promising therapeutic method to inhibit EGFR-mediated BC.

Keywords: Breast cancer, phenolic compounds, glabridin, signaling pathways, epidermal growth factor receptor, molecular dynamics simulation.

Key, T.J.; Verkasalo, P.K.; Banks, E. Epidemiology of breast cancer. Lancet Oncol., 2001, 2(3), 133-140.
[] [PMID: 11902563]
Schroeder, J.A.; Lee, D.C. Transgenic mice reveal roles for TGFalpha and EGF receptor in mammary gland development and neoplasia. J. Mammary Gland Biol. Neoplasia, 1997, 2(2), 119-129.
[] [PMID: 10882298]
Hampton, K.K.; Craven, R.J. Pathways driving the endocytosis of mutant and wild-type EGFR in cancer. Oncoscience, 2014, 1(8), 504-512.
[] [PMID: 25594057]
Lo, H.W.; Hsu, S.C.; Hung, M.C. EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization. Breast Cancer Res. Treat., 2006, 95(3), 211-218.
[] [PMID: 16261406]
Bhargava, R.; Gerald, W.L.; Li, A.R.; Pan, Q.; Lal, P.; Ladanyi, M.; Chen, B. EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations. Mod. Pathol., 2005, 18(8), 1027-1033.
[] [PMID: 15920544]
Dandawate, P.R.; Subramaniam, D.; Jensen, R.A.; Anant, S. Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy. Semin. Cancer Biol., 2016, 40-41(41), 192-208.
[] [PMID: 27609747]
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod., 2016, 79(3), 629-661.
[] [PMID: 26852623]
Siddiqui, J.; Singh, A.; Chagtoo, M.; Singh, N.; Godbole, M.; Chakravarti, B. Phytochemicals for breast cancer therapy: current status and future implications. Curr. Cancer Drug Targets, 2015, 15(2), 116-135.
[] [PMID: 25544650]
Aggarwal, B.B.; Sethi, G.; Baladandayuthapani, V.; Krishnan, S.; Shishodia, S. Targeting cell signaling pathways for drug discovery: an old lock needs a new key. J. Cell Biochem., 2007, 102(3), 580-592.
[] [PMID: 17668425]
Li, X.; Yang, C.; Wan, H.; Zhang, G.; Feng, J.; Zhang, L.; Chen, X.; Zhong, D.; Lou, L.; Tao, W.; Zhang, L. Discovery and development of pyrotinib: A novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer. Eur. J. Pharm. Sci., 2017, 110(110), 51-61.
[] [PMID: 28115222]
Burris, H.A., III Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist, 2004, 9(S3)(Suppl. 3), 10-15.
[] [PMID: 15163842]
Bose, P.; Ozer, H. Neratinib: an oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer. Expert Opin. Investig. Drugs, 2009, 18(11), 1735-1751.
[] [PMID: 19780706]
Liu, B.; Diaz Arguello, O.A.; Chen, D.; Chen, S.; Saber, A.; Haisma, H.J. CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation. PLoS One, 2020, 15(5), e0232985.
[] [PMID: 32413049]
Kulke, M.H.; Blaszkowsky, L.S.; Ryan, D.P.; Clark, J.W.; Meyerhardt, J.A.; Zhu, A.X.; Enzinger, P.C.; Kwak, E.L.; Muzikansky, A.; Lawrence, C.; Fuchs, C.S. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J. Clin. Oncol., 2007, 25(30), 4787-4792.
[] [PMID: 17947726]
Janjigian, Y.Y.; Smit, E.F.; Groen, H.J.M.; Horn, L.; Gettinger, S.; Camidge, D.R.; Riely, G.J.; Wang, B.; Fu, Y.; Chand, V.K.; Miller, V.A.; Pao, W. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov., 2014, 4(9), 1036-1045.
[] [PMID: 25074459]
Hiscox, S.; Morgan, L.; Barrow, D.; Dutkowski, C.; Wakeling, A.; Nicholson, R.I. Tamoxifen resistance in breast cancer cells is accompanied by an enhanced motile and invasive phenotype: Inhibition by gefitinib (‘Iressa’, ZD1839). Clin. Exp. Metastasis, 2004, 21(3), 201-212.
[] [PMID: 15387370]
Waddell, T.; Chau, I.; Cunningham, D.; Gonzalez, D.; Okines, A.F.C.; Wotherspoon, A.; Saffery, C.; Middleton, G.; Wadsley, J.; Ferry, D.; Mansoor, W.; Crosby, T.; Coxon, F.; Smith, D.; Waters, J.; Iveson, T.; Falk, S.; Slater, S.; Peckitt, C.; Barbachano, Y.; Barbachano, Y. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol., 2013, 14(6), 481-489.
[] [PMID: 23594787]
Taurin, S.; Allen, K.M.; Scandlyn, M.J.; Rosengren, R.J. Raloxifene reduces triple-negative breast cancer tumor growth and decreases EGFR expression. Int. J. Oncol., 2013, 43(3), 785-792.
[] [PMID: 23842642]
Dittmann, K.H.; Mayer, C.; Ohneseit, P.A.; Raju, U.; Andratschke, N.H.; Milas, L.; Rodemann, H.P. Celecoxib induced tumor cell radiosensitization by inhibiting radiation induced nuclear EGFR transport and DNA-repair: a COX-2 independent mechanism. Int. J. Radiat. Oncol. Biol. Phys., 2008, 70(1), 203-212.
[] [PMID: 17996386]
Balakrishnan, S.; Mukherjee, S.; Das, S.; Bhat, F.A.; Raja Singh, P.; Patra, C.R.; Arunakaran, J. Gold nanoparticles- conjugated quercetin induces apoptosis via inhibition of EGFR/PI3K/Akt-mediated pathway in breast cancer cell lines (MCF-7 and MDA-MB-231). Cell Biochem. Funct., 2017, 35(4), 217-231.
[] [PMID: 28498520]
Starok, M.; Preira, P.; Vayssade, M.; Haupt, K.; Salomé, L.; Rossi, C. EGFR inhibition by curcumin in cancer cells: a dual mode of action. Biomacromolecules, 2015, 16(5), 1634-1642.
[] [PMID: 25893361]
Zhu, L.; Shen, X.B.; Yuan, P.C.; Shao, T.L.; Wang, G.D.; Liu, X.P. Arctigenin inhibits proliferation of ER-positive breast cancer cells through cell cycle arrest mediated by GSK3-dependent cyclin D1 degradation. Life Sci., 2020, 256, 117983.
[] [PMID: 32565252]
Lee, J.; Kim, J.H. Kim. Kaempferol inhibits pancreatic cancer cell growth and migration through the blockade of EGFR-related pathway in vitro. PLoS One, 2016, 11(5), e0155264.
[] [PMID: 27175782]
Jaman, M.S.; Sayeed, M.A. Ellagic acid, sulforaphane, and ursolic acid in the prevention and therapy of breast cancer: current evidence and future perspectives. Breast Cancer, 2018, 25(5), 517-528.
[] [PMID: 29725861]
Baraya, Y.S.; Wong, K.K.; Yaacob, N.S.; Nik, S.Y. The immunomodulatory potential of selected bioactive plant-based compounds in breast cancer: a review. Anticancer. Agents Med. Chem., 2017, 17(6), 770-783.
[PMID: 27539316]
Zhang, L.; Chen, H.; Wang, M.; Song, X.; Ding, F.; Zhu, J.; Li, X. Effects of glabridin combined with 5-fluorouracil on the proliferation and apoptosis of gastric cancer cells. Oncol. Lett., 2018, 15(5), 7037-7045.
[] [PMID: 29725429]
Orry, A.J.W.; Abagyan, R.A.; Cavasotto, C.N. Structure-based development of target-specific compound libraries. Drug Discov. Today, 2006, 11(5-6), 261-266.
[] [PMID: 16580603]
Chandrika, B.B.; Steephan, M.; Kumar, T.R.S.; Sabu, A.; Haridas, M. Hesperetin and Naringenin sensitize HER2 positive cancer cells to death by serving as HER2 Tyrosine Kinase inhibitors. Life Sci., 2016, 160, 47-56.
[] [PMID: 27449398]
Jung, S.K.; Kim, J.E.; Lee, S.Y.; Lee, M.H.; Byun, S.; Kim, Y.A.; Lim, T.G.; Reddy, K.; Huang, Z.; Bode, A.M.; Lee, H.J.; Lee, K.W.; Dong, Z. The P110 subunit of PI3-K is a therapeutic target of acacetin in skin cancer. Carcinogenesis, 2014, 35(1), 123-130.
[] [PMID: 23913940]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[] [PMID: 10592235]
O’Boyle, N.M.; Banck, M.; James, C.A.; Morley, C.; Vandermeersch, T.; Hutchison, G.R. Open Babel: An open chemical toolbox. J. Cheminform., 2011, 3(1), 33.
[] [PMID: 21982300]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[] [PMID: 19399780]
Lipinski, C.A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[] [PMID: 24981612]
Jiang, D.; Li, X.; Wang, H.; Shi, Y.; Xu, C.; Lu, S.; Huang, J.; Xu, Y.; Zeng, H.; Su, J.; Hou, Y.; Tan, L. The prognostic value of EGFR overexpression and amplification in Esophageal squamous cell Carcinoma. BMC Cancer, 2015, 15(1), 377.
[] [PMID: 25953424]
Bowers, K.J.; Chow, D.E.; Xu, H.; Dror, R.O.; Eastwood, M.P.; Gregersen, B.A.; Klepeis, J.L.; Kolossvary, I.; Moraes, M.A.; Sacerdoti, F.D.; Salmon, J.K. Scalable algorithms for molecular dynamics simulations on commodity clusters. SC’06: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing, 2006, , pp. 43-43.
Chow, E.; Rendleman, C.A.; Bowers, K.J.; Dror, R.O.; Hughes, D.H.; Gullingsrud, J.; Sacerdoti, F.D.; Shaw, D.E. Desmond performance on a cluster of multicore processors. DE Shaw Research Technical Report DESRES/TR--2008-01, 2008.
Shivakumar, D.; Williams, J.; Wu, Y.; Damm, W.; Shelley, J.; Sherman, W. Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J. Chem. Theory Comput., 2010, 6(5), 1509-1519.
[] [PMID: 26615687]
Jorgensen, W.L.; Chandrasekhar, J.; Madura, J.D.; Impey, R.W.; Klein, M.L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys., 1983, 79(2), 926-935.
Martyna, G.J.; Tobias, D.J.; Klein, M.L. Constant pressure molecular dynamics algorithms. J. Chem. Phys., 1994, 101(5), 4177-4189.
Martyna, G.J.; Klein, M.L.; Tuckerman, M. Nosé–Hoover chains: The canonical ensemble via continuous dynamics. J. Chem. Phys., 1992, 97(4), 2635-2643.
Toukmaji, A.Y.; Board, J.A., Jr Ewald summation techniques in perspective: A survey. Comput. Phys. Commun., 1996, 95(2-3), 73-92.
Kagami, L.P.; das Neves, G.M.; Timmers, L.F.S.M.; Caceres, R.A.; Eifler-Lima, V.L. Geo-Measures: A PyMOL plugin for protein structure ensembles analysis. Comput. Biol. Chem., 2020, 87, 107322.
[] [PMID: 32604028]
Banerjee, P.; Eckert, A.O.; Schrey, A.K.; Preissner, R. ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res., 2018, 46(W1), W257-W263.
[] [PMID: 29718510]
Leelananda, S.P.; Lindert, S. Computational methods in drug discovery. Beilstein J. Org. Chem., 2016, 12(1), 2694-2718.
[] [PMID: 28144341]
Aggarwal, B.B.; Kumar, A.; Bharti, A.C. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res., 2003, 23(1A), 363-398.
[PMID: 12680238]
Aggarwal, B.B. Nuclear factor-κB. Cancer Cell, 2004, 6(3), 203-208.
[] [PMID: 15380510]
Maadwar, S.; Galla, R. Cytotoxic oxindole derivatives: in vitro EGFR inhibition, pharmacophore modeling, 3D-QSAR and molecular dynamics studies. J. Recept. Signal Transduct. Res., 2019, 39(5-6), 460-469.
[] [PMID: 31814499]

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