Affinity for Estrogen Receptor α (ERα) in a trans-Stilbene Derivative Containing a Pyridoxine Fragment
https://doi.org/10.26907/2542-064X.2024.2.255-265
Abstract
Molecular targets for a promising antitumor agent based on trans-stilbene containing a pyridoxine fragment were identified. The lead compound, (E)-6-(3,4-dimethoxystyryl)-2,2,5,8-tetramethyl-4H-[1,3] dioxino[4,5-c]pyridine, was found to selectively induce apoptosis in MCF-7 breast adenocarcinoma cells overexpressing estrogen receptor, but not in MDA-MB-231 cells negative for estrogen receptor. The mechanism by which the novel trans-stilbene derivative acts as a selective estrogen receptor modulator was analyzed, and the affinity for human estrogen receptor α (ERα) was assessed by fluorescence polarization. Unlike its structural analogs—tamoxifen and raloxifene, the lead compound showed no affinity for ERα and did not form complexes with it. Therefore, it was concluded that the selective action of the pyridoxine-containing derivative of trans-stilbene on estrogen-positive breast cancer cells occurs through an alternative mechanism. The EC50 values for the displacement of the fluorescent ligand from the ERα active site were 22, 120, and 595 nM for estradiol, raloxifene, and tamoxifen, respectively.
Keywords
trans-stilbenes,
pyridoxine,
estrogen receptor α,
tamoxifen,
raloxifene,
complexation,
fluorescence polarization
Supporting agencies: This study was supported by the subsidy allocated to Kazan Federal University for the state assignment in the sphere of scientific activities (project no. FZSM2023-0010).
About the Authors
O. V. Bondar
Kazan Federal University
Russian Federation
Russian Federation
Kazan, 420008
R. Karut
Kazan Federal University
Russian Federation
Russian Federation
Kazan, 420008
O. A. Mostovaya
Kazan Federal University
Russian Federation
Russian Federation
Kazan, 420008
M. V. Pugachev
Kazan Federal University
Russian Federation
Russian Federation
Kazan, 420008
A. G. Iksanova
Kazan Federal University
Russian Federation
Russian Federation
Kazan, 420008
Yu. G. Shtyrlin
Kazan Federal University
Russian Federation
Russian Federation
Kazan, 420008
References
1. Diez-Perez A. Selective estrogen receptor modulators (SERMS). Arq. Bras. Endocrinol. Metabol., 2006, vol. 50, no. 4, pp. 720–734. https://doi.org/10.1590/s0004-27302006000400017.
2. Pugachev M.V., Pavelyev R.S., Nguyen T.N.T., Gabbasova R.R., Bulatov T.M., Iksanova A.G., Aljondi B., Bondar O.V., Grishaev D.Yu., Yamaleeva Z.R., Kataeva O.N., Nikishova T.V., Balakin K.V., Shtyrlin Yu.G. Synthesis, antitumor activity and structure-activity studies of novel pyridoxine-based bioisosteric analogs of estradiol. Bioorg. Med. Chem., 2021, vol. 30, art. 115957. https://doi.org/10.1016/j.bmc.2020.115957.
3. Pugachev M.V., Nguyen T.T.N., Bulatov T.M., Pavelyev R.S., Iksanova A.G., Bondar O.V., Balakin K.V., Shtyrlin Yu.G. Synthesis and antitumor activity of novel pyridoxine-based bioisosteric analogs of trans-stilbenes. J. Chem., 2017, vol. 2017, art. 8281518. https://doi.org/10.1155/2017/8281518.
4. Jordan V.C. A current view of tamoxifen for the treatment and prevention of breast cancer. Br. J. Pharmacol., 1993, vol. 110, no. 2, pp. 507–517. https://doi.org/10.1111/j.1476-5381.1993.tb13840.x.
5. Klinge C.M. Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res., 2001, vol. 29, no. 14, pp. 2905–2919. https://doi.org/10.1093/nar/29.14.2905.
6. Gruvberger-Saal S.K., Bendahl P.-O., Saal L.H., Laakso M., Hegardt C., Edén P., Peterson C., Malmström P., Isola J., Borg Å., Fernö M. Estrogen receptor β expression is associated with tamoxifen response in ERα-negative breast carcinoma. Clin. Cancer Res., 2007, vol. 13, no. 7, pp. 1987–1994. https://doi.org/10.1158/1078-0432.CCR-06-1823.
7. Howell A., Cuzick J., Baum M., Buzdar A., Dowsett M., Forbes J.F., Hoctin-Boes G., Houghton J., Locker G.Y., Tobias J.S. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet, 2005, vol. 365, no. 9453, pp. 60–62. https://doi.org/10.1016/S0140-6736(04)17666-6.
8. Heringa M. Review on raloxifene: Profile of a selective estrogen receptor modulator. Int. J. Clin. Pharmacol. Ther., 2003, vol. 41, no. 8, pp. 331–345. https://doi.org/10.5414/cpp41331.
9. Bryant H.U., Glasebrook A.L., Yang N.N., Sato M. An estrogen receptor basis for raloxifene action in bone. J. Steroid Biochem. Mol. Biol., 1999, vol. 69, nos. 1–6, pp. 37–44. https://doi.org/10.1016/s0960-0760(98)00147-2.
10. Brzozowski A.M., Pike A.C.W., Dauter Z., Hubbard R.E., Bonn T., Engström O., Öhman L., Greene G.L., Gustafsson J.-Å., Carlquist M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature, 1997, vol. 389, no. 6652, pp. 753–758. https://doi.org/10.1038/39645.
11. Martinkovich S., Shah D., Planey S.L., Arnott J. Selective estrogen receptor modulators: Tissue specificity and clinical utility. Clin. Interventions Aging., 2014, vol. 9, pp. 1437–1452. https://doi.org/10.2147/CIA.S66690.
12. Liu H., Park W.-C., Bentrem D.J., McKian K.P., de Los Reyes A., Loweth J.A., Schafer J.M., Zapf J.W., Jordan V.C. Structure-function relationships of the raloxifene-estrogen receptor-α complex for regulating transforming growth factor-α expression in breast cancer cells. J. Biol. Chem., 2002, vol. 277, no. 11, pp. 9189–9198. https://doi.org/10.1074/jbc.M108335200.
13. Weatherman R.V., Clegg N.J., Scanlan T.S. Differential SERM activation of the estrogen receptors (ERα and ERβ) at AP-1 sites. Chem. Biol., 2001, vol. 8, no. 5, pp. 427–436. https://doi.org/10.1016/S1074-5521(01)00025-4.
14. PolarScreen™ ER Alpha Competitor Assay, Red. User manual. Publ.: MAN0009428. Rev.: A.0. URL: https://www.thermofisher.com/document-connect/document-connect.html?url=https://assets.thermofisher.com/TFS-Assets%2FLSG%2Fmanuals%2Fpolarscreen_er_alpha_red_man.pdf.
15. Lin A.H.Y., Li R.W.S., Ho E.Y.W., Leung G.P.H., Leung S.W.S., Vanhoutte P.M., Man R.Y.K. Differential ligand binding affinities of human estrogen receptor-α isoforms. PLoS ONE, 2013, vol. 8, no. 4, art. e63199. https://doi.org/10.1371/journal.pone.0063199.
16. Blair R.M., Fang H., Branham W.S., Hass B.S., Dial S.L., Moland C.L., Tong W., Shi L., Perkins R., Sheehan D.M. The estrogen receptor relative binding affinities of 188 natural and xenochemicals: Structural diversity of ligands. Toxicol. Sci., 2000, vol. 54, no. 1, pp. 138–153. https://doi.org/10.1093/toxsci/54.1.138.
17. Radin D.P., Patel P. Delineating the molecular mechanisms of tamoxifen’s oncolytic actions in estrogen receptor-negative cancers. Eur. J. Pharmacol., 2016, vol. 781, pp. 173–180. https://doi.org/10.1016/j.ejphar.2016.04.017.
Review
For citations:
Bondar O.V., Karut R., Mostovaya O.A., Pugachev M.V., Iksanova A.G., Shtyrlin Yu.G. Affinity for Estrogen Receptor α (ERα) in a trans-Stilbene Derivative Containing a Pyridoxine Fragment. Uchenye Zapiski Kazanskogo Universiteta Seriya Estestvennye Nauki. 2024;166(2):255-265. (In Russ.) https://doi.org/10.26907/2542-064X.2024.2.255-265
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