Computer-Aided Drug Repurposing: A Cyclooxygenase-2 Inhibitor Celecoxib as a Ligand for Estrogen Receptor Alpha

https://doi.org/10.22146/ijc.21196

Enade Perdana Istyastono(1*), Florentinus Dika Octa Riswanto(2), Sri Hartati Yuliani(3)

(1) Division of Drug Design and Discovery, Faculty of Pharmacy, Sanata Dharma University, Paingan, Maguwohardjo, Depok, Yogyakarta 55282
(2) Division of Food and Drug Safety, Quality and Efficacy, Faculty of Pharmacy, Sanata Dharma University, Paingan, Maguwohardjo, Depok, Yogyakarta 55282
(3) Division of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Sanata Dharma University, Paingan, Maguwohardjo, Depok, Yogyakarta 55282
(*) Corresponding Author

Abstract


A cyclooxygenase-2 (COX-2) inhibitor celecoxib has been previously reported to have cytotoxic activities towards gastric, prostate, ovarian, colon and breast cancer cell lines. This article reports that the cytotoxic activities of celecoxib could be resulted from its activity as a potent ligand for estrogen receptor alpha (ERα). Aided by molecular docking simulations, an in silico test to examine whether celecoxib is a ligand for estrogen receptor alpha (ERα) was performed followed by in vitro test employing cytotoxic assay using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method. The compound was extracted from Celebrex®. Measured by using UV spectrophotometric method at 255.5 nm, it was identified that the content of celecoxib was 102.15 mg/271.48 mg capsule content. The in silico test indicated that celecoxib is a potent ligand for ERα. This finding was confirmed experimentally by an in vitro test that celecoxib has a comparable activity as an ERα ligand to tamoxifen, a drug of choice for breast cancer treatment.

Keywords


cyclooxygenase-2; estrogen receptor alpha; molecular docking; celecoxib

Full Text:

Full Text Pdf


References

[1] Sadée, W., and Bohn, L., 2006, Mol. Intervention, 6 (4), 196–198.

[2] Penning, T.D., Talley, J.J., Bertenshaw, S.R., Carter, J.S., Collins, P.W., Docter, S., Graneto, M.J., Lee, L.F., Malecha, J.W., Miyashiro, J.M., Rogers, R.S., Rogier, D.J., Yu, S.S., Anderson, G.D., Burton, E.G., Cogburn, J.N., Gregory, S.A., Koboldt, C.M., Perkins, W.E., Seibert, K., Veenhuizen, A.W., Zhang, Y.Y., and Isakson, P.C., 1997, J. Med. Chem., 40 (9), 1347–1365.

[3] Jendrossek, V., 2013, Cancer Lett., 332 (2), 313–324.

[4] Liu, D., Hu, G., Long, G., Qiu, H., Mei, Q., and Hu, G., 2012, Acta Pharmacol. Sin., 33 (5), 682–690.

[5] Winfield, L.L., and Payton-Stewart, F., 2012, Future Med. Chem., 4 (3), 361–383.

[6] Rimon, G., Sidhu, R.S., Lauver, D.A., Lee, J.Y., Sharma, N.P., Yuan, C., Frieler, R.A., Trievel, R.C., Lucchesi, B.R., and Smith, W.L., 2010, Proc. Natl. Acad. Sci. U.S.A., 107 (1), 28–33.

[7] Chakraborti, A.K., Garg, S.K., Kumar, R., Motiwala, H.F., and Jadhavar, P.S., 2010, Curr. Med. Chem., 17 (15), 1563–1593.

[8] Williams, C.S., Watson, A.J.M., and Sheng, H., 2000, Cancer Res., 60 (21), 6045–6051.

[9] Patel, M.I., Subbaramaiah, K., Du, B., Chang, M., Yang, P., Newman, R.A., Cardo, C.C., Thaler, H.T., and Dannenberg, A.J., 2005, Clin. Cancer Res., 11 (5), 1999–2007.

[10] Turini, M.E., and DuBois, R.N., 2002, Annu. Rev. Med., 53, 35–57.

[11] Wang, Y.X., Gao, J.X., Wang, X.Y., Zhang, L., and Liu, C.M., 2012, Tumor Biol., 33 (4), 957–966.

[12] Mouridsen, H., Giobbie-Hurder, A., Goldhirsch, A., Thürlimann, B., Paridaens, R., Smith, I., Mauriac, L., Forbes, J.F., Price, K.N., Regan, M.M., Gelber, R.D., and Coates, A.S., 2009, N. Engl. J. Med., 361 (8), 766–776.

[13] Desta, Z., Ward, B.A., Soukhova, N.V., and Flockhart, D.A., 2004, J. Pharmacol. Exp. Ther., 310 (3), 1062–1075.

[14] Irwin, J.J., Sterling, T., Mysinger, M.M., Bolstad, E.S., and Coleman, R.G., 2012, J. Chem. Inf. Model., 52 (7), 1757–1768.

[15] Istyastono, E.P., 2013, Virtual Screening on ZINC Drug Database to Discover Novel Antagonists for Estrogen Receptor α, Sanata Dharma University Research Grant Final Report, Universitas Sanata Dharma, Yogyakarta.

[16] Bisson, W.H., Cheltsov, A.V., Bruey-Sedano, N., Lin, B., Chen, J., Goldberger, N., May, L.T., Christopoulos, A., Dalton, J.T., Sexton, P.M., Zhang, X., and Abagyan, R. 2007, Proc. Natl. Acad. Sci. U.S.A., 104 (29), 11927–11932.

[17] Anita, Y., Radifar, M., Kardono, L., Hanafi, M., and Istyastono, E.P., 2012, Bioinformation, 8 (19), 901–906.

[18] Huang, N., Shoichet, B.K., and Irwin, J.J., 2006, J. Med. Chem., 49 (23), 6789–6801.

[19] Radifar, M., Yuniarti, N., and Istyastono, E.P., 2013, Bioinformation, 9 (6), 325–328.

[20] Setiawati, A., Riswanto, F.D.O., Yuliani, S.H., and Istyastono, E.P., 2014, Indones. J. Chem., 14 (2), 103–108.

[21] Radifar, M., Yuniarti, N., and Istyastono, E.P., 2013, Indones. J. Chem., 13 (3), 283–286.

[22] Irwin, J.J., and Shoichet, B.K., 2005, J. Chem. Inf. Model., 45 (1), 177–182.

[23] Setiawati, A., Riswanto, F.O.D., Yuliani, S.H., and Istyastono, E.P., 2014, Indonesian J. Pharm., 25 (3), 119–124.

[24] Korb, O., Stützle, T., and Exner, T.E., 2009, J. Chem. Inf. Model., 49 (1), 84–96.

[25] Korb, O., Stützle, T., and Exner, T.E., 2007, Proc. IEEE Swarm Intell. Symp., 1 (2), 115–134.

[26] R Development Core Team, 2008, R: A Language and Environment for Statistical Computing, Vienna. http://www.r-project.org.

[27] Salentin, S., Haupt, V.J., Daminelli, S., and Schroeder, M., 2014, Prog. Biophys. Mol. Biol., 116 (2-3), 174–186.

[28] Kreidenweiss, A., Kremsner, P.G., and Mordmüller, B., 2008, Malar. J., 7 (187), 1–8.

[29] Appiah-Opong, R., Commandeur, J.N.M., van Vugt-Lussenburg, B., and Vermeulen, N.P.E., 2007, Toxicology, 235 (1-2), 83–91.

[30] Istyastono, E.P., de Graaf, C., de Esch, I.J.P., and Leurs, R., 2011, Curr. Top. Med. Chem., 11 (6), 661–679.

[31] Istyastono, E.P., Nijmeijer, S., Lim, H.D., van de Stolpe, A., Roumen, L., Kooistra, A.J., Vischer, H.F., de Esch, I.J.P., Leurs, R., and de Graaf, C., 2011, J. Med. Chem., 54 (23), 8136–8147.

[32] de Graaf, C., Kooistra, A.J., Vischer, H.F., Katritch, V., Kuijer, M., Shiroishi, M., Iwata, S., Shimamura, T., Stevens, R.C., de Esch, I.J.P., Leurs, R., 2011, J. Med. Chem., 54 (23), 8195–8206.

[33] Sirci, F., Istyastono, E.P., Vischer, H.F., Kooistra, A.J., Nijmeijer, S., Kuijer, M., Wijtmans, M., Mannhold, R., Leurs, R., de Esch, I.J.P., and de Graaf, C., 2012, J. Chem. Inf. Model., 52 (12), 3308–3324.

[34] Kufareva, I., Katritch, V., Stevens, R.C., and Abagyan, R., 2014, Structure, 22 (8), 1120–1139.

[35] Schultes, S., Nijmeijer, S., Engelhardt, H., Kooistra, A.J., Vischer, H.F., de Esch, I.J.P., Haaksma, E.E.J., Leurs, R., and de Graaf, C., 2013, Med. Chem. Commun., 4 (1), 193–204.

[36] Mysinger, M.M., Carchia, M., Irwin, J.J., and Shoichet, B.K., 2012, J. Med. Chem., 55 (14), 6582–6594.

[37] Katritch, V., Jaakola, V., Lane, J.R., Lin, J., Ijzerman, A.P., Yeager, M., Kufareva, I., Stevens, R.C., and Abagyan, R., 2010, J. Med. Chem., 53 (4), 1799–1809.

[38] Kolb, P., Rosenbaum, D.M., Irwin, J.J., Fung, J.J., Kobilka, B.K., and Shoichet, B.K., 2009, Proc. Natl. Acad. Sci. U.S.A., 106 (16), 6843–6848.

[39] Carlsson, J., Coleman, R.G., Setola, V., Irwin, J.J., Fan, H., Schlessinger, A., Sali, A., Roth, B.L., and Shoichet, B.K., 2011, Nat. Chem. Biol., 7 (11), 769–778.

[40] Lim, H.D., Istyastono, E.P., van de Stolpe, A., Romeo, G., Gobbi, S., Schepers, M., Lahaye, R., Menge, W.M.B.P., Zuiderveld, O.P., Jongejan, A., Smits, R.A., Bakker, R.A., Haaksma, E.E.J., Leurs, R., and de Esch, I.J.P., 2009, Bioorg. Med. Chem., 17 (11), 3987–3994.

[41] Strasser, A., 2009, Expert Opin. Drug Discovery, 4 (10), 1061–1075.

[42] Smits, R.A., Adami, M., Istyastono, E.P., Zuiderveld, O.P., van Dam, C.M.E., de Kanter, F.J.J., Jongejan, A., Coruzzi, G., Leurs, R., and de Esch, I.J.P., 2010, J. Med. Chem., 53 (6), 2390–2400.

[43] Xiang, Y., Hou, Z., and Zhang, Z., 2012, Chem. Biol. Drug Des., 79 (5), 760–770.

[44] Appiah-Opong, R., Commandeur, J.N.M., Istyastono, E.P., Bogaards, J.J., and Vermeulen, N.P.E., 2009, Xenobiotica, 39 (4), 302–311.

[45] Schultes, S., Engelhardt, H., Roumen, L., Zuiderveld, O.P., Haaksma, E.E.J., de Esch, I.J.P., Leurs, R., and de Graaf, C., 2013, ChemMedChem, 8 (1), 49–53.

[46] Engelhardt, H., Schultes, S., de Graaf, C., Nijmeijer, S., Vischer, H.F., Zuiderveld, O.P., Dobler, J., Stachurski, K., Mayer, M., Arnhof, H., Scharn, D., Haaksma, E.E.J., de Esch, I.J.P., and Leurs, R., 2013, J. Med. Chem., 56 (11), 4264–4276.

[47] Lim, H.D., de Graaf, C., Jiang, W., Sadek, P., McGovern, P.M., Istyastono, E.P., Bakker, R. A, de Esch, I.J.P., Thurmond, R.L., and Leurs, R., 2010, Mol. Pharmacol., 77 (5), 734–743.

[48] Marcou, G., and Rognan, D., 2007, J. Chem. Inf. Model., 47 (1), 195-207.

[49] Schultes, S., Kooistra, A., Vischer, H., Nijmeijer, S., Haaksma, E., Leurs, R., de Esch, I., and de Graaf, C., 2015, J. Chem. Inf. Model., 55 (5), 1030–1044.

[50] Istyastono, E.P., Kooistra, A.J., Vischer, H., Kuijer, M., Roumen, L., Nijmeijer, S., Smits, R., de Esch, I., Leurs, R., and de Graaf, C., 2015, Med. Chem. Commun., 6, 1003–1017.

[51] Revathi, R., Perumal, R.V., Sudharshini, S., Ansar, A.M., Thilagalakshmi, A., and Dinesh, A.P., 2011, Int. J. Pharm. Sci. Lett., 1 (2), 49–50.

[52] Riswanto, F.O.D., Lukitaningsih, R.R.E., and Martono, S., 2015, Indones. J. Chem., 15 (1), 9–15.

[53] Kealey, D., and Haines, P.J., 2002, Instant Notes Analytical Chemistry, BIOS Scientific Publishers Ltd., Oxford, 225–226.

[54] Ermer, J., and Miller, J.H., 2005, Method Validation in Pharmaceutical Analysis: A Guide to Best Practice, Wiley-VCH Verlag GmbH & Co., Weinheim, 87–90.

[55] González, A.G., and Herrador, M.A., 2007, TrAC, Trends Anal. Chem., 26 (3), 227–238.

[56] Brooks, S.C., Locke, E.R., and Soule, H.D., 1973, J. Biol. Chem., 248 (17), 6251–6253.

[57] Vidhya, N., and Devaraj, S.N., 2011, Indian J. Exp. Biol., 49 (11), 871–878.



DOI: https://doi.org/10.22146/ijc.21196

Article Metrics

Abstract views : 3290 | views : 2903


Copyright (c) 2015 Indonesian Journal of Chemistry

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

 

Indonesian Journal of Chemistry (ISSN 1411-9420 /e-ISSN 2460-1578) - Chemistry Department, Universitas Gadjah Mada, Indonesia.

Web Analytics View The Statistics of Indones. J. Chem.