danДоклады Национальной академии наук БеларусиDoklady of the National Academy of Sciences of Belarus1561-83232524-2431The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1561-8323-2024-68-1-28-35dan-1172Research ArticleХИМИЯCHEMISTRYВлияние эфиров брассиностероидов с салициловой, янтарной и индолилуксусной кислотой на рост опухолевых клетокEffect of brassinosteroid esters with salicylic, succinic, and indolylacetic acids on the tumor cell growthПанибратО. В.PanibratA. V.

Панибрат Олеся Владимировна – канд. хим. наук, ст. науч. сотрудник.

Ул. Купревича, 5/2, 220084, Минск

Panibrat Alesia V. – Ph. D. (Chemistry), Senior Researcher.

5/2, Kuprevich Str., 220084, Minsk

panibrat@iboch.byТрифоноваА. Р.TryfanavaA. R.

Трифонова Алина Руслановна – мл. науч. сотрудник.

Ул. Купревича, 5/2, 220084, Минск

Tryfanava Alina R. – Junior Researcher.

5/2, Kuprevich Str., 220084, Minsk

alina25060180@mail.ruСавочкаО. П.SavachkaA. P.

Савочка Олег Петрович – мл. науч. сотрудник.

Ул. Купревича, 5/2, 220084

Savachka Aleh P. – Junior Researcher.

5/2, Kuprevich Str., 220084, Minsk

oleg.brsv@mail.ruЛитвиновскаяР. П.LitvinovskayaR. P.

Литвиновская Раиса Павловна – д-р хим. наук, профессор, гл. науч. сотрудник.

Ул. Купревича, 5/2, 220084, Минск

litvin@iboch.byЧащинаН. М.ChashchinaN. M.

Чащина Наталья Михайловна – ст. науч. сотрудник.

Ул. Купревича, 5/2, 220084, Минск

Chashchina Natalia M. – Senior Researcher.

5/2, Kuprevich Str., 220084, Minsk

chashchyna@iboch.byЖабинскийВ. Н.ZhabinskiiV. N.

Жабинский Владимир Николаевич – член-корреспондент, д-р хим. наук, профессор, гл. науч. сотрудник.

Ул. Купревича, 5/2, 220084, Минск

Zhabinskii Vladimir N. – Corresponding Member, D. Sc. (Chemistry), Chief Researcher, Professor.

5/2, Kuprevich Str., 220084, Minsk

vz@iboch.byХрипачВ. А.KhripachV. A.

Хрипач Владимир Александрович – академик, д-р хим. наук, профессор, заведующий лабораторией.

Ул. Купревича, 5/2, 220084, Минск

Khripach Vladimir A. – Academician, D. Sc. (Chemistry), Professor, Head of the Laboratory.

5/2, Kuprevich Str., 220084, Minsk

khripach@iboch.byИнститут биоорганической химии Национальной академии наук БеларусиInstitute of Bioorganic Chemistry of the National Academy of Sciences of Belarus2024040320246812835Copyright © Панибрат О.В., Трифонова А.Р., Савочка О.П., Литвиновская Р.П., Чащина Н.М., Жабинский В.Н., Хрипач В.А., 20242024Панибрат О.В., Трифонова А.Р., Савочка О.П., Литвиновская Р.П., Чащина Н.М., Жабинский В.Н., Хрипач В.А.Panibrat A.V., Tryfanava A.R., Savachka A.P., Litvinovskaya R.P., Chashchina N.M., Zhabinskii V.N., Khripach V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://doklady.belnauka.by/jour/article/view/1172

Работа проведена с целью изучения влияния новых производных брассиностероидов – сложных эфиров с салициловой, янтарной и индолилуксусной кислотой, на рост опухолевых клеток, на распределение их по фазам клеточного цикла и определение типа клеточной гибели. Показано, что активность синтезированных новых соединений существенно различается в зависимости от характера замещения в стероидном ядре, составляя в случае салицилатов эпибрассинолида и эпикастастерона величину IC50 < 10 мкМ, одновременно вызывая остановку клеточного цикла в фазе G0/G1, снижение митохондриального потенциала и апоптоз опухолевых клеток. Полученные результаты свидетельствуют о высокой активности салицилатов, эффективно подавляющих рост всех изученных видов опухолей, и перспективности поиска новых противоопухолевых агентов в этом ряду соединений.

The aim of this work is to study the effect of new derivatives of brassinosteroids – their esters with salicylic, succinic, and indolylacetic acids on the growth of tumor cells, on their distribution by cell cycle phases and determination of the type of cell death. It was shown that the activity of the new synthesized compounds differed significantly depending on the substitution nature in the steroid nucleus, amounting to <10 µM in the case of epibrassinolide and epicastasterone salicylates, simultaneously causing the cycle arrest in the G0/G1 phase, a mitochondrial potential decrease, and apoptosis of tumor cells. The results obtained indicate the high activity of salicylates, which effectively suppress the growth of the all studied types of tumors, and the prospects of finding new antitumor agents in this series of compounds.

брассиностероидыэфиры биогенных кислотжизнеспособность опухолевых клетокклеточный циклапоптозbrassinosteroidsbiogenic acid esterstumor cell viabilitycell cycleapoptosisРабота выполнена при финансовой поддержке Белорусского республиканского фонда фундаментальных исследований (договор № Х23РНФ-087)The work was sponsored by the Belarusian Republican Foundation for Fundamental Research (agreement no. X23РНФ-087)ReferencesKhripach V. A., Zhabinskii V. N., de Groot A. Brassinosteroids. A New Class of Plant Hormones. San Diego, 1999. 456 p. https://doi.org/10.1016/b978-0-12-406360-0.x5000-xKhripach V. A., Zhabinskii V. N., de Groot A. Brassinosteroids. A New Class of Plant Hormones. San Diego, 1999. 456 p. https://doi.org/10.1016/b978-0-12-406360-0.x5000-xLitvinovskaya R. P., Minin P. S., Raiman M. E., Zhilitskaya G. A., Kurtikova A. L., Kozharnovich K. G., Derevyanchuk M. V., Kravets V. S., Khripach V. A. Indolyl-3-acetoxy derivatives of brassinosteroids: synthesis and growth-regulating activity. Chemistry of Natural Compounds, 2013, vol. 49, pp. 478–485. https://doi.org/10.1007/s10600-013-0643-8Litvinovskaya R. P., Minin P. S., Raiman M. E., Zhilitskaya G. A., Kurtikova A. L., Kozharnovich K. G., Derevyanchuk M. V., Kravets V. S., Khripach V. A. Indolyl-3-acetoxy derivatives of brassinosteroids: synthesis and growth-regulating activity. Chemistry of Natural Compounds, 2013, vol. 49, pp. 478–485. https://doi.org/10.1007/s10600-013-0643-8Litvinovskaya R. P., Manzhalesava N. E., Savachka A. P., Khripach V. A. Synthesis of brassinosteroid tetrahemisuccinates and their effect on the initial growth of spring barley plants. Russian Journal of Bioorganic Chemistry, 2022, vol. 48, pp. 543–547. https://doi.org/10.1134/s1068162022030128Litvinovskaya R. P., Manzhalesava N. E., Savachka A. P., Khripach V. A. Synthesis of brassinosteroid tetrahemisuccinates and their effect on the initial growth of spring barley plants. Russian Journal of Bioorganic Chemistry, 2022, vol. 48, pp. 543–547. https://doi.org/10.1134/s1068162022030128Litvinovskaya R. P., Vayner A. A., Zhylitskaya H. A., Kolupaev Yu. E., Savachka A. P., Khripach V. A. Synthesis and stress-protective action on plants of brassinosteroid conjugates with salicylic acid. Chemistry of Natural Compounds, 2016, vol. 52, pp. 452–457. https://doi.org/10.1007/s10600-016-1671-yLitvinovskaya R. P., Vayner A. A., Zhylitskaya H. A., Kolupaev Yu. E., Savachka A. P., Khripach V. A. Synthesis and stress-protective action on plants of brassinosteroid conjugates with salicylic acid. Chemistry of Natural Compounds, 2016, vol. 52, pp. 452–457. https://doi.org/10.1007/s10600-016-1671-yZhabinskii V. N., Khripach N. B., Khripach V. A. Steroid plant hormones: effects outside plant kingdom. Steroids, 2015, vol. 97, pp. 87–97. https://doi.org/10.1016/j.steroids.2014.08.025Zhabinskii V. N., Khripach N. B., Khripach V. A. Steroid plant hormones: effects outside plant kingdom. Steroids, 2015, vol. 97, pp. 87–97. https://doi.org/10.1016/j.steroids.2014.08.025Malíková J., Swaczynová J., Kolář Z., Strnad M. Anticancer and antiproliferative activity of natural brassinosteroids. Phytochemistry, 2008, vol. 69, no. 2, pp. 418–426. https://doi.org/10.1016/j.phytochem.2007.07.028Malíková J., Swaczynová J., Kolář Z., Strnad M. Anticancer and antiproliferative activity of natural brassinosteroids. Phytochemistry, 2008, vol. 69, no. 2, pp. 418–426. https://doi.org/10.1016/j.phytochem.2007.07.028Al-Nasiry S., Geusens N., Hanssens M., Luyten C., Pijnenborg R. The use of Alamar Blue assay for quantitative analysis of viability, migration and invasion of choriocarcinoma cells. Human Reproduction, 2007, vol. 22, no. 5, pp. 1304–1309. https://doi.org/10.1093/humrep/dem011Al-Nasiry S., Geusens N., Hanssens M., Luyten C., Pijnenborg R. The use of Alamar Blue assay for quantitative analysis of viability, migration and invasion of choriocarcinoma cells. Human Reproduction, 2007, vol. 22, no. 5, pp. 1304–1309. https://doi.org/10.1093/humrep/dem011Riccardi C., Nicoletti I. Analysis of apoptosis by propidium iodide staining and flow cytometry. Nature Protocols, 2006, vol. 1, pp. 1458–1461. https://doi.org/10.1038/nprot.2006.238Riccardi C., Nicoletti I. Analysis of apoptosis by propidium iodide staining and flow cytometry. Nature Protocols, 2006, vol. 1, pp. 1458–1461. https://doi.org/10.1038/nprot.2006.238Witte I., Horke S. Assessment of endoplasmic reticulum stress and the unfolded protein response in endothelial cells. Methods in Enzymology, 2011, vol. 489, pp. 127–146. https://doi.org/10.1016/b978-0-12-385116-1.00008-xWitte I., Horke S. Assessment of endoplasmic reticulum stress and the unfolded protein response in endothelial cells. Methods in Enzymology, 2011, vol. 489, pp. 127–146. https://doi.org/10.1016/b978-0-12-385116-1.00008-xRieger A. M., Nelson K. L., Konowalchuk J. D., Barreda D. R. Modified annexin V/propidium iodide apoptosis assay for accurate assessment of cell death. Journal of Visualized Experiments: JoVE, 2011, vol. 50, art. 2597. https://doi.org/10.3791/2597Rieger A. M., Nelson K. L., Konowalchuk J. D., Barreda D. R. Modified annexin V/propidium iodide apoptosis assay for accurate assessment of cell death. Journal of Visualized Experiments: JoVE, 2011, vol. 50, art. 2597. https://doi.org/10.3791/2597Tardito S., Isella C., Medico E., Marchiò L., Bevilacqua E., Hatzoglou M., Bussolati O., Franchi-Gazzola R. The thioxotriazole copper (II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. Journal of Biological Chemistry, 2009, vol. 284, no. 36, pp. 24306–24319. https://doi.org/10.1074/jbc.m109.026583Tardito S., Isella C., Medico E., Marchiò L., Bevilacqua E., Hatzoglou M., Bussolati O., Franchi-Gazzola R. The thioxotriazole copper (II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. Journal of Biological Chemistry, 2009, vol. 284, no. 36, pp. 24306–24319. https://doi.org/10.1074/jbc.m109.026583Bourzikat O., El Abbouchi A., Ghammaz H., El Brahmi N., El Fahime E., Paris A., Daniellou R., Suzenet F., Guillaumet G., El Kazzouli S. Synthesis, Anticancer Activities and Molecular Docking Studies of a Novel Class of 2-Phenyl5,6,7,8-tetrahydroimidazo [1,2-b]pyridazine Derivatives Bearing Sulfonamides. Molecules, 2022, vol. 27, no. 16, art. 5238. https://doi.org/10.3390/molecules27165238Bourzikat O., El Abbouchi A., Ghammaz H., El Brahmi N., El Fahime E., Paris A., Daniellou R., Suzenet F., Guillaumet G., El Kazzouli S. Synthesis, Anticancer Activities and Molecular Docking Studies of a Novel Class of 2-Phenyl5,6,7,8-tetrahydroimidazo [1,2-b]pyridazine Derivatives Bearing Sulfonamides. Molecules, 2022, vol. 27, no. 16, art. 5238. https://doi.org/10.3390/molecules27165238McGahon A. J., Brown D. G., Martin S. J., Amarante-Mendes G. P., Cotter T. G., Cohen G. M., Green D. R. Downregulation of Bcr-Abl in K562 cells restores susceptibility to apoptosis: characterization of the apoptotic death. Cell Death and Differentiation, 1997, vol. 4, pp. 95–104. https://doi.org/10.1038/sj.cdd.4400213McGahon A. J., Brown D. G., Martin S. J., Amarante-Mendes G. P., Cotter T. G., Cohen G. M., Green D. R. Downregulation of Bcr-Abl in K562 cells restores susceptibility to apoptosis: characterization of the apoptotic death. Cell Death and Differentiation, 1997, vol. 4, pp. 95–104. https://doi.org/10.1038/sj.cdd.4400213Dachineni R., Kumar D. R., Callegari E., Kesharwani S. S., Sankaranarayanan R., Seefeldt T., Tummala H., Bhat G. J. Salicylic acid metabolites and derivatives inhibit CDK activity: Novel insights into aspirin’s chemopreventive effects against colorectal cancer. International Journal of Oncology, 2017, vol. 51, no. 6, pp. 1661–1673. https://doi.org/10.3892/ijo.2017.4167Dachineni R., Kumar D. R., Callegari E., Kesharwani S. S., Sankaranarayanan R., Seefeldt T., Tummala H., Bhat G. J. Salicylic acid metabolites and derivatives inhibit CDK activity: Novel insights into aspirin’s chemopreventive effects against colorectal cancer. International Journal of Oncology, 2017, vol. 51, no. 6, pp. 1661–1673. https://doi.org/10.3892/ijo.2017.4167Ding L., Cao J., Lin W., Chen H., Xiong X., Ao H., Yu M., Lin J., Cui Q. The roles of cyclin-dependent kinases in cell-cycle progression and therapeutic strategies in human breast cancer. International Journal of Molecular Sciences, 2020, vol. 21, no. 6, art. 1960. https://doi.org/10.3390/ijms21061960Ding L., Cao J., Lin W., Chen H., Xiong X., Ao H., Yu M., Lin J., Cui Q. The roles of cyclin-dependent kinases in cell-cycle progression and therapeutic strategies in human breast cancer. International Journal of Molecular Sciences, 2020, vol. 21, no. 6, art. 1960. https://doi.org/10.3390/ijms21061960

The authors declare that there are no conflicts of interest present.