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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

Prospects of Wedelolactone as a Chemotherapeutic Agent in Gynecological Cancers; Clue From its In Vitro and In Silico Investigation

Author(s): Sadia Sarwar*, Tauqeer Amed, Neelum Gul Qazi, Jun Qing Yu and Fazlul Huq

Volume 16, Issue 4, 2020

Page: [365 - 375] Pages: 11

DOI: 10.2174/1573409915666191015113134

Price: $65

Abstract

Background: Identification and development of new drug candidates to be used singly or in combination therapy is critical in anticancer research. In recent years, accumulating evidence encouraged us to investigate the anti-proliferative effects of a small and emerging phytochemical Wedelolactone (WDL) in estrogen-dependent and independent multiple gynecological tumor models.

Objective: The aim of this study was to investigate the growth inhibitory effect of WDL on estrogen- dependent and independent gynecological cell lines and to explore its inhibitory potential towards key targets through in silico study.

Methods: Cytotoxicity of WDL was investigated in human breast and ovarian cancer cell lines (MCF-7 and SKOV3) through 3-(4,5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) reduction assay. Epigallocatechingallate (EGCG) was used as reference natural compound while cisplatin was taken as a standard clinical agent. Both WDL and EGCG in combination with cisplatin were also evaluated for their combined growth inhibitory potential in MCF-7 cells. WDL was also evaluated in silico against key factors including braf kinases, CDPK, ERα, aromatase, topoisomerase II and dihydrofolate reductase (DHFR) playing pivotal roles in driving multiple tumors.

Results and Discussion: The IC50 value of WDL was 25.77 ± 4.82 μM and 33.64 ± 1.45 μM in MCF-7 and SKOV-3 respectively. The binding energy order was as follows; WDL: DHFR >Braf kinases > CDPK; aromatase > topoisomerase II> ERα > NFkB > alkaline phosphatase; EGCG dihydrofolatereductase (DHFR) > aromatase >CDPK > topoisomerase II > braf kinases > alkaline phosphatase > CDPK > ERα > NFkB.

Conclusion: We identified WDL as a cytotoxic agent in breast and ovarian tumor models with the potential to inhibit multiple targets in the oncogenic pathway including estrogen receptor ERα, as depicted through its in silico study. Based on our own research findings and from literature evidence, we conclude that further research should be encouraged to investigate different aspects of wedelolactone as an additional agent to be combined with antiestrogen/endocrine therapy.

Keywords: Cytotoxic agent, ovarian cancer, wedelolactone, epigallocatechingallate, topoisomerase, phytochemicals.

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[1]
Boyle, P.; Levin, B. World cancer report 2008; IARC Press: Geneva, 2008.
[2]
Wooster, R.; Weber, B.L. Breast and ovarian cancer. N. Engl. J. Med., 2003, 348(23), 2339-2347.
[http://dx.doi.org/10.1056/NEJMra012284] [PMID: 12788999]
[3]
Anastassiadis, T.; Deacon, S.W.; Devarajan, K.; Ma, H.; Peterson, J.R. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 2011, 29(11), 1039-1045.
[http://dx.doi.org/10.1038/nbt.2017] [PMID: 22037377]
[4]
Gottesman, M.M.; Fojo, T.; Bates, S.E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer, 2002, 2(1), 48-58.
[http://dx.doi.org/10.1038/nrc706] [PMID: 11902585]
[5]
Jadhav, V.; Thorat, R.; Kadam, V.; Salaskar, K. Chemical composition, pharmacological activities of Eclipta alba. J. Pharm. Res., 2009, 2(8), 1229-1231.
[6]
Chen, H.; Landen, C.N.; Li, Y.; Alvarez, R.D.; Tollefsbol, T.O. Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation. Exp. Cell Res., 2013, 319(5), 697-706.
[http://dx.doi.org/10.1016/j.yexcr.2012.12.026] [PMID: 23333498]
[7]
Nehybova, T.; Smarda, J.; Daniel, L.; Brezovsky, J.; Benes, P. Wedelolactone induces growth of breast cancer cells by stimulation of estrogen receptor signalling. J. Steroid Biochem. Mol. Biol., 2015, 152(1), 76-83.
[http://dx.doi.org/10.1016/j.jsbmb.2015.04.019] [PMID: 25934092]
[8]
Mors, W.B.; do Nascimento, M.C.; Parente, J.P.; da Silva, M.H.; Melo, P.A.; Suarez-Kurtz, G. Neutralization of lethal and myotoxic activities of South American rattlesnake venom by extracts and constituents of the plant Eclipta prostrata (Asteraceae). Toxicon, 1989, 27(9), 1003-1009.
[http://dx.doi.org/10.1016/0041-0101(89)90151-7] [PMID: 2799833]
[9]
Singh, B.; Saxena, A.K.; Chandan, B.K.; Agarwal, S.G.; Anand, K.K. In vivo hepatoprotective activity of active fraction from ethanolic extract of Eclipta alba leaves. Indian J. Physiol. Pharmacol., 2001, 45(4), 435-441.
[PMID: 11883149]
[10]
Horn-Ross, P.L.; Barnes, S.; Lee, M.; Coward, L.; Mandel, J.E.; Koo, J.; John, E.M.; Smith, M. Assessing phytoestrogen exposure in epidemiologic studies: development of a database (United States). Cancer Causes Control, 2000, 11(4), 289-298.
[http://dx.doi.org/10.1023/A:1008995606699] [PMID: 10843440]
[11]
Albini, A.; Rosano, C.; Angelini, G.; Amaro, A.; Esposito, A.I.; Maramotti, S.; Noonan, D.M.; Pfeffer, U. Exogenous hormonal regulation in breast cancer cells by phytoestrogens and endocrine disruptors. Curr. Med. Chem., 2014, 21(9), 1129-1145.
[http://dx.doi.org/10.2174/0929867321666131129124640] [PMID: 24304271]
[12]
Liu, Y-Q.; Hong, Z-L.; Zhan, L-B.; Chu, H-Y.; Zhang, X-Z.; Li, G-H. Wedelolactone enhances osteoblastogenesis by regulating Wnt/β-catenin signaling pathway but suppresses osteoclastogenesis by NF-κB/c-fos/NFATc1 pathway. Sci. Rep., 2016, 6(6), 32260.
[http://dx.doi.org/10.1038/srep32260] [PMID: 27558652]
[13]
Dallakyan, S.; Olson, A.J. Small-Molecule Library Screening by Docking with PyRx.Chemical Biology; Hempel, J.; Wil-liams, C; Hong, C., Ed.; Humana Press: New York, 2015, Vol. 1263, pp. 243-250.
[14]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[15]
Morris, G.M.; Goodsell, D.S.; Halliday, R.S.; Huey, R.; Hart, W.E.; Belew, R.K.; Olson, A.J. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem., 1998, 19(14), 1639-1662.
[http://dx.doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639:AID-JCC10>3.0.CO;2-B]
[16]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[17]
Chou, T. Relationships between inhibition constants and fractional inhibition in enzyme-catalyzed reactions with different numbers of reactants, different reaction mechanisms, and different types and mechanisms of inhibition. Mol. Pharmacol., 1974, 10(2), 235-247.
[PMID: 4212316]
[18]
Chou, T.C. Derivation and properties of Michaelis-Menten type and Hill type equations for reference ligands. J. Theor. Biol., 1976, 59(2), 253-276.
[http://dx.doi.org/10.1016/0022-5193(76)90169-7] [PMID: 957690]
[19]
Bano, S.; Khan, A.U.; Asghar, F.; Usman, M.; Badshah, A.; Ali, S. Computational and pharmacological evaluation of fer-rocene-based acyl ureas and homoleptic cadmium carboxylate derivatives for anti-diabetic potential. Front. Pharmacol., 2018, 8, 1001.
[http://dx.doi.org/10.3389/fphar.2017.01001] [PMID: 29387011]
[20]
Morris, G. M.; Lim-Wilby, M. Molecular docking. Molecular modeling of proteins, 2008, 365-382.
[http://dx.doi.org/10.1007/978-1-59745-177-2_19]
[21]
Wang, R.; Lai, L.; Wang, S. Further development and validation of empirical scoring functions for structure-based binding affinity prediction. J. Comput. Aided Mol. Des., 2002, 16(1), 11-26.
[http://dx.doi.org/10.1023/A:1016357811882] [PMID: 12197663]
[22]
Patil, R.; Das, S.; Stanley, A.; Yadav, L.; Sudhakar, A.; Varma, A.K. Optimized hydrophobic interactions and hydrogen bonding at the target-ligand interface leads the pathways of drug-designing. PLoS One, 2010, 5(8) e12029
[http://dx.doi.org/10.1371/journal.pone.0012029] [PMID: 20808434]
[23]
Dembo, A.G.; Aledort, E.S.; Greene, G.L. Preventing estrogen receptor alpha-positive breast cancer outgrowth with the use of hormone replacement therapy, Proceedings of the AACR Annual Meeting, Chicago, USA, April 14-18,2018. Cancer Res., 2018, 78, 242.
[http://dx.doi.org/10.1158/1538-7445.AM2018-948]
[24]
Monsif, B.; Maysoun, S.; Jane, C.; Natalia, M.; Fangxian, S.; Malvika, K.; Zhuyan, G.; Stephane, P.; Mikhail, L.; Dietmar, H.; Hui, C.; Laurent, B.; Francisco, A.; Christoph, W. Youssef, El-A.; Sylvie, Vincent.; Frank, H.; Gary, M.; Lau-rent, S.; Vicky, R.; Hong, C.; Karl, H.; Chris, S.; Patrick, C.; Joanne, L.; Carlos, G-E.; Laurent, D. SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust antitumor efficacy and limited cross-resistance in ER+ breast cancer, Proceedings of the AACR An nual Meeting, Chicago, USA, April 14-18, 2018. Cancer Res., 2018, 78, 241.
[http://dx.doi.org/10.1158/1538-7445.AM2018-943]
[25]
Kuiper, G.G.; Lemmen, J.G.; Carlsson, B.; Corton, J.C.; Safe, S.H.; van der Saag, P.T.; van der Burg, B.; Gustafsson, J.A. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology, 1998, 139(10), 4252-4263.
[http://dx.doi.org/10.1210/endo.139.10.6216] [PMID: 9751507]
[26]
Lin, F.M.; Chen, L.R.; Lin, E.H.; Ke, F.C.; Chen, H.Y.; Tsai, M.J.; Hsiao, P.W. Compounds from Wedelia chinensis synergistically suppress androgen activity and growth in prostate cancer cells. Carcinogenesis, 2007, 28(12), 2521-2529.
[http://dx.doi.org/10.1093/carcin/bgm137] [PMID: 17942463]
[27]
Herrera-Abreu, M.T.; Palafox, M.; Asghar, U.; Rivas, M.A.; Cutts, R.J.; Garcia-Murillas, I.; Pearson, A.; Guzman, M.; Rodriguez, O.; Grueso, J.; Bellet, M.; Cortés, J.; Elliott, R.; Pancholi, S.; Baselga, J.; Dowsett, M.; Martin, L.A.; Turner, N.C.; Serra, V. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor–positive breast cancer. Cancer Res., 2016, 76(8), 2301-2313.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-0728] [PMID: 27020857]
[28]
Millimouno, F.M.; Dong, J.; Yang, L.; Li, J.; Li, X. Targeting apoptosis pathways in cancer and perspectives with natural compounds from mother nature. Cancer Prev. Res. (Phila.), 2014, 7(11), 1081-1107.
[http://dx.doi.org/10.1158/1940-6207.CAPR-14-0136] [PMID: 25161295]
[29]
Sarwar, S.; Yu, J.Q.; Huq, F. In: Cisplatin in combination with a potential antiestrogen wedelolactone applied to different gy-naecological tumor models, Proceedings of the AACR Annual Meeting,Philadelphia, USA, April 18-22, 2015. Cancer Res., 2015, 75, 5554.
[http://dx.doi.org/10.1158/1538-7445.AM2015-5554]

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