References

oncotomsk

Сибирский онкологический журнал

Siberian journal of oncology

1814-48612312-3168

Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences

10.21294/1814-4861-2024-23-4-125-140

oncotomsk-3199

Research Article

ОБЗОРЫ

REVIEWS

Подходы к противоопухолевой терапии на основе модуляции метилирования ДНК

Approaches to anticancer therapy based on modulation of DNA methylation

https://orcid.org/0000-0003-0896-2952

Максимова

В. П.

Maksimova

V. P.

Максимова Варвара Павловна, младший научный сотрудник лаборатории канцерогенных веществ отдела химического канцерогенеза

Researcher ID (WOS): S-7580-2019

Author ID (Scopus): 57195322203

115478, г. Москва, Каширское шоссе, 24

Varvara P. Maksimova, Junior Researcher, Carcinogenic Substances Laboratory, Department of Chemical Carcinogenesis

Researcher ID (WOS): S-7580-2019

Author ID (Scopus): 57195322203

23, Kashirskoye Shosse, Moscow, 115478

https://orcid.org/0000-0001-6820-4198

Макусь

Ю. В.

Makus

J. V.

Макусь Юлия Валерьевна, практикант лаборатории механизмов химического канцерогенеза отдела химического канцерогенеза; студентка 1-го курса магистратуры факультета анализа данных в биологии и медицине

Researcher ID (WOS): AAK-2145-2020

Author ID (Scopus): 57218900186

115478, г. Москва, Каширское шоссе, 24

101000, г. Москва, ул. Мясницкая, 20

Yulia V. Makus, Trainee of the Laboratory of Mechanisms of Chemical Carcinogenesis, Department of Chemical Carcinogenesis; 1st year Master’s student of the Faculty of Data Analysis in Biology and Medicine

Researcher ID (WOS): AAK-2145-2020

Author ID (Scopus): 57218900186

23, Kashirskoye Shosse, Moscow, 115478

20, Myasnickaya St., Moscow, 101000

https://orcid.org/0000-0002-7301-605X

Попова

В. Г.

Popova

V. G.

Попова Валерия Геннадьевна, лаборант-исследователь лаборатории канцерогенных веществ отдела химического канцерогенеза

Researcher ID (WOS): AAL-7244-2021

Author ID (Scopus): 57226857087

115478, г. Москва, Каширское шоссе, 24

117198, г. Москва, ул. Миклухо-Маклая, 6

Valeria G. Popova, Research Laboratory Assistant, Carcinogenic Substances Laboratory, Department of Chemical Carcinogenesis

Researcher ID (WOS): AAL-7244-2021

Author ID (Scopus): 57226857087

23, Kashirskoye Shosse, Moscow, 115478

6, Miklukho-Maklaya St., Moscow, 117198

https://orcid.org/0000-0001-9525-0771

Усалка

О. Г.

Usalka

O. G.

Усалка Ольга Геннадьевна, практикант лаборатории канцерогенных веществ отдела химического канцерогенеза; практикант факультета биологии

Researcher ID (WOS): AAK-2008-2020

Author ID (Scopus): 57218894338

115478, г. Москва, Каширское шоссе, 24

02155, г. Медфорд, Бостон авеню, 200

Olga G. Usalka, Trainee of the Laboratory of Carcinogenic Substances, Department of Chemical Carcinogenesis; Trainee at the Faculty of Biology

Researcher ID (WOS): AAK-2008-2020

Author ID (Scopus): 57218894338

23, Kashirskoye Shosse, Moscow, 115478

200, Boston Ave., Medford, 02155

https://orcid.org/0000-0002-3167-7204

Белицкий

Г. А.

Belitsky

G. A.

Белицкий Геннадий Альтерович, доктор медицинских наук, профессор, главный научный консультант лаборатории механизмов химического канцерогенеза отдела химического канцерогенеза

Researcher ID (WOS): L-3062-2015

115478, г. Москва, Каширское шоссе, 24

Gennady A. Belitsky, MD, Professor, Chief Scientific Advisor, Laboratory of Mechanisms of Chemical Carcinogenesis, Department of Chemical Carcinogenesis

Researcher ID (WOS): L-3062-2015

23, Kashirskoye Shosse, Moscow, 115478

https://orcid.org/0000-0002-9710-8178

Якубовская

М. Г.

Yakubovskaya

M. G.

Якубовская Марианна Геннадьевна, доктор медицинских наук, заведующая отделом химического канцерогенеза

Researcher ID (WOS): R-6984-2016

Author ID (Scopus): 57217461641

115478, г. Москва, Каширское шоссе, 24

117198, г. Москва, ул. Миклухо-Маклая, 6

Marianna G. Yakubovskaya, MD, DSc, Head of the Department of Chemical Carcinogenesis

Researcher ID (WOS): R-6984-2016

Author ID (Scopus): 57217461641

23, Kashirskoye Shosse, Moscow, 115478

6, Miklukho-Maklaya St., Moscow, 117198

https://orcid.org/0000-0002-8599-6833

Кирсанов

К. И.

Kirsanov

K. I.

Кирсанов Кирилл Игоревич, доктор биологических наук, заведующий лабораторией канцерогенных веществ отдела химического канцерогенеза; ассистент кафедры общей врачебной практики

Researcher ID (WOS): L-3062-2015

Author ID (Scopus): 36461343900

115478, г. Москва, Каширское шоссе, 24

117198, г. Москва, ул. Миклухо-Маклая, 6

Kirill I. Kirsanov, DSc, Head of the Carcinogenic Substances Laboratory, Department of Chemical Carcinogenesis; Assistant, Department of General Medical Practice

Researcher ID (WOS): L-3062-2015

Author ID (Scopus): 36461343900

23, Kashirskoye Shosse, Moscow, 115478

6, Miklukho-Maklaya St., Moscow, 117198

Kkirsanov85@yandex.ru

ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина»РоссияN.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of RussiaRussian Federation

ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина»; НИУ «Высшая школа экономики»РоссияN.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia; National Research University Higher School of EconomicsRussian Federation

ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина»; ФГАОУ ВО «Российский университет дружбы народов»РоссияN.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia; RUDN UniversityRussian Federation

ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина»; Университет ТафтсаРоссияN.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia; Tufts UniversityRussian Federation

2024

09092024

234125140

2024

Максимова В.П., Макусь Ю.В., Попова В.Г., Усалка О.Г., Белицкий Г.А., Якубовская М.Г., Кирсанов К.И.

Maksimova V.P., Makus J.V., Popova V.G., Usalka O.G., Belitsky G.A., Yakubovskaya M.G., Kirsanov K.I.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.siboncoj.ru/jour/article/view/3199

Актуальность. Метилирование ДНК – важнейший механизм эпигенетической регуляции транскрипции. Нарушения в механизме метилирования ДНК ассоциированы с различными злокачественными новообразованиями (ЗНО), такими как острый миелоидный лейкоз, рак молочной железы, рак предстательной железы и др. Влияние на функциональное состояние ферментов ДНК-метилтрансфераз (DNMTs) и белков семейства ТЕТ (TETs), регулирующих метилирование и деметилирование ДНК, является основой подхода эпигенетической противоопухолевой терапии. В обзоре рассматриваются проблемы и перспективы применения нуклеозидных и ненуклеозидных ингибиторов DNMTs, а также ингибиторов TETs. Представлена оценка результатов клинических исследований эффективности ингибиторов DNMTs, применяемых индивидуально и в составе комбинированной химиотерапии, проведенных за последние 15 лет. Материал и методы. Поиск источников проводили в системах PubMed, ScienceDirect, Web of Science, eLibrary, CyberLeninka. В анализе использовано более 700 публикаций, в обзор включены преимущественно работы последних 10 лет. Ряд статей, опубликованных ранее 2015 г., использован для исторической справки. Результаты. Представлена информация о современных достижениях по разработке и изучению эпигенетически активных соединений, действие которых направлено на регуляцию метилирования ДНК. Представлены данные об эффектах in vitro и in vivo агентов, рассматриваемых для применения в терапии различных ЗНО. Кроме того, приведены данные клинических испытаний наиболее перспективных эпигенетических модуляторов.

Background. DNA methylation is a crucial mechanism of epigenetic regulation of transcription. Disturbances in DNA methylation mechanism are associated with various malignancies such as acute myeloid leukaemia, breast cancer, prostate cancer, etc. Influencing the functional status of DNA methyltransferases (DNMTs) enzymes and TET family proteins (TETs), which regulate DNA methylation and demethylation, is the basis of epigenetic anticancer therapy approach. In this review, we have considered the challenges and prospects of nucleoside and non-nucleoside inhibitors of DNMTs as well as TETs inhibitors. The results of clinical trials on the efficacy of DNMTs inhibitors used individually and as part of combination chemotherapy conducted over the last 15 years are also evaluated. Material and Methods. Sources were searched in PubMed, ScienceDirect, Web of Science, eLibrary, CyberLeninka. More than 700 publications were used in the analysis, but the review included mainly works of the last 10 years. A number of articles published earlier than 2015 were used for historical reference. Results. The review provides information on current advances in the development and study of epigenetically active compounds whose action is aimed at the regulation of DNA methylation. Data on the in vitro and in vivo effects of agents considered for use in the therapy of various malignancies are presented. In addition, the data of clinical trials of the most promising epigenetic modulators are presented.

противоопухолевая терапияметилирование ДНКингибиторы DNMTsингибиторы TETsклинические испытания

antitumour therapyDNA methylationDNMTs inhibitorsTETs inhibitorsclinical trials

Финансирование Работа выполнена при финансовой поддержке Российского научного фонда (проект № 21-75- 10163).

This work was financially supported by the Russian Science Foundation (project No. 21-75-10163).

References1

Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022; 12(1): 31–46. doi: 10.1158/2159-8290.CD-21-1059.

Cheng Y., He C., Wang M., Ma X., Mo F., Yang S., Han J., Wei X. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target Ther. 2019; 4: 62. doi: 10.1038/s41392-019-0095-0.

Максимова В.П., Усалка О.Г., Макусь Ю.В., Попова В.Г., Трапезникова Е.С., Хайриева Г.И., Сагитова Г.Р., Жидкова Е.М., Прус А.Ю., Якубовская М.Г., Кирсанов К.И. Нарушение метилирования ДНК при злокачественных новообразованиях. Успехи молекулярной онкологии. 2022; 9(4): 24–40. doi: 10.17650/2313-805X-2022-9-4-24-40.

Maksimova V.P., Usalka O.G., Makus Yu.V., Popova V.G., Trapeznikova E.S., Khayrieva G.I., Sagitova G.R., Zhidkova E.M., Prus A.Yu., Yakubovskaya M.G., Kirsanov K.I. Aberrations of DNA methylation in cancer. Advances in Molecular Oncology. 2022; 9(4): 24–40. (in Russian). doi: 10.17650/2313-805X-2022-9-4-24-40.

Kohli R.M., Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature. 2013; 502(7472): 472–9. doi: 10.1038/nature12750.

Takeshima H., Niwa T., Yamashita S., Takamura-Enya T., Iida N., Wakabayashi M., Nanjo S., Abe M., Sugiyama T., Kim Y.J., Ushijima T. TET repression and increased DNMT activity synergistically induce aberrant DNA methylation. J Clin Invest. 2020; 130(10): 5370–9. doi: 10.1172/JCI124070.

Liu X.L., Liu H.Q., Li J., Mao C.Y., He J.T., Zhao X. Role of epigenetic in leukemia: From mechanism to therapy. Chem Biol Interact. 2020; 317. doi: 10.1016/j.cbi.2020.108963.

Stresemann C., Lyko F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008; 123(1): 8–13. doi: 10.1002/ijc.23607.

Yang X., Lay F., Han H., Jones P.A. Targeting DNA methylation for epigenetic therapy. Trends Pharmacol Sci. 2010; 31(11): 536–46. doi: 10.1016/j.tips.2010.08.001.

Gu X., Tohme R., Tomlinson B., Sakre N., Hasipek M., Durkin L., Schuerger C., Grabowski D., Zidan A.M., Radivoyevitch T., Hong C., Carraway H., Hamilton B., Sobecks R., Patel B., Jha B.K., Hsi E.D., Maciejewski J., Saunthararajah Y. Decitabine- and 5-azacytidine resistance emerges from adaptive responses of the pyrimidine metabolism network. Leukemia. 2021; 35(4): 1023–36. doi: 10.1038/s41375-020-1003-x.

Malik P., Cashen A.F. Decitabine in the treatment of acute myeloid leukemia in elderly patients. Cancer Manag Res. 2014; 6: 53–61. doi: 10.2147/CMAR.S40600.

Kaminskas E., Farrell A.T., Wang Y.C., Sridhara R., Pazdur R. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005; 10(3): 176–82. doi: 10.1634/theoncologist.10-3-176.

Tallman M.S., Wang E.S., Altman J.K., Appelbaum F.R., Bhatt V.R., Bixby D., Coutre S.E., De Lima M., Fathi A.T., Fiorella M., Foran J.M., Hall A.C., Jacoby M., Lancet J., LeBlanc T.W., Mannis G., Marcucci G., Martin M.G., Mims A., O'Donnell M.R., Olin R., Peker D., Perl A., Pollyea D.A., Pratz K., Prebet T., Ravandi F., Shami P.J., Stone R.M., Strickland S.A., Wieduwilt M., Gregory K.M.; OCN; Hammond L., Ogba N. Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019; 17(6): 721–49. doi: 10.6004/jnccn.2019.0028.

Савченко В.Г., Паровичникова Е.Н., Афанасьев Б.В., Грицаев С.В., Семочкин С.В., Бондаренко С.Н., Троицкая В.В., Соколов А.Н., Кузьмина Л.А., Клясова Г.А., Гапонова Т.В., Баранова О.Ю., Лапин В.А., Константинова Т.С., Самойлова О.С., Капорская Т.С., Шатохин С.A. Клинические рекомендации по диагностике и лечению острых лимфобластных лейкозов взрослых. Национальное гематологическое общество. 2014. 65 с.

Wei A.H., Döhner H., Pocock C., Montesinos P., Afanasyev B., Dombret H., Ravandi F., Sayar H., Jang J.H., Porkka K., Selleslag D., Sandhu I., Turgut M., Giai V., Ofran Y., Kizil Çakar M., Botelho de Sousa A., Rybka J., Frairia C., Borin L., Beltrami G., Čermák J., Ossenkoppele G.J., La Torre I., Skikne B., Kumar K., Dong Q., Beach C.L., Roboz G.J., for the QUAZAR AML-001 Trial Investigators†. Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. N Engl J Med. 2020; 383(26): 2526–37. doi: 10.1056/NEJMoa2004444.

Montesinos P., Recher C., Vives S., Zarzycka E., Wang J., Bertani G., Heuser M., Calado R.T., Schuh A.C., Yeh S.P., Daigle S.R., Hui J., Pandya S.S., Gianolio D.A., de Botton S., Döhner H. Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med. 2022; 386(16): 1519–31. doi: 10.1056/NEJMoa2117344.

Niemeyer C.M., Flotho C., Lipka D.B., Starý J., Rössig C., Baruchel A., Klingebiel T., Micalizzi C., Michel G., Nysom K., Rives S., Schmugge Liner M., Zecca M., Schönung M., Baumann I., Nöllke P., Benettaib B., Biserna N., Poon J., Simcock M., Patturajan M., Menezes D., Gaudy A., van den Heuvel-Eibrink M.M., Locatelli F. Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML001 trial. Blood Adv. 2021; 5(14): 2901–8. doi: 10.1182/bloodadvances.2020004144.

Jabbour E., Issa J.P., Garcia-Manero G., Kantarjian H. Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008; 112(11): 2341–51. doi: 10.1002/cncr.23463.

Briski R., Garcia-Manero G., Kantarjian H., Ravandi F. The history of oral decitabine/cedazuridine and its potential role in acute myeloid leukemia. Ther Adv Hematol. 2023; 14. doi: 10.1177/20406207231205429.

Pollyea D.A., Winters A., McMahon C., Schwartz M., Jordan C.T., Rabinovitch R., Abbott D., Smith C.A., Gutman J.A. Venetoclax and azacitidine followed by allogeneic transplant results in excellent outcomes and may improve outcomes versus maintenance therapy among newly diagnosed AML patients older than 60. Bone Marrow Transplant. 2022; 57(2): 160–6. doi: 10.1038/s41409-021-01476-7.

Sekeres M.A., Watts J., Radinoff A., Sangerman M.A., Cerrano M., Lopez P.F., Zeidner J.F., Campelo M.D., Graux C., Liesveld J., Selleslag D., Tzvetkov N., Fram R.J., Zhao D., Bell J., Friedlander S., Faller D.V., Adès L. Randomized phase 2 trial of pevonedistat plus azacitidine versus azacitidine for higher-risk MDS/CMML or low-blast AML. Leukemia. 2021; 35(7): 2119–24. doi: 10.1038/s41375-021-01125-4. Erratum in: Leukemia. 2021; 35(12): 3637. doi: 10.1038/s41375-021-01473-1.

DiNardo C.D., Schuh A.C., Stein E.M., Montesinos P., Wei A.H., de Botton S., Zeidan A.M., Fathi A.T., Kantarjian H.M., Bennett J.M., Frattini M.G., Martin-Regueira P., Lersch F., Gong J., Hasan M., Vyas P., Döhner H. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221- AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021; 22(11): 1597–608. doi: 10.1016/S1470-2045(21)00494-0.

Ohanian M., Garcia-Manero G., Levis M., Jabbour E., Daver N., Borthakur G., Kadia T., Pierce S., Burger J., Richie M.A., Patel K., Andreeff M., Estrov Z., Cortes J., Kantarjian H., Ravandi F. Sorafenib Combined with 5-azacytidine in Older Patients with Untreated FLT3-ITD Mutated Acute Myeloid Leukemia. Am J Hematol. 2018; 93(9): 1136–41. doi: 10.1002/ajh.25198.

Hu J., Wang X., Chen F., Ding M., Dong M., Yang W., Yin M., Wu J., Zhang L., Fu X., Sun Z., Li L., Wang X., Li X., Guo S., Zhang D., Lu X., Leng Q., Zhang M., Zhu L., Zhang X., Chen Q. Combination of Decitabine and a Modified Regimen of Cisplatin, Cytarabine and Dexamethasone: A Potential Salvage Regimen for Relapsed or Refractory Diffuse Large B-Cell Lymphoma After Second-Line Treatment Failure. Front Oncol. 2021; 11. doi: 10.3389/fonc.2021.687374.

Buocikova V., Tyciakova S., Pilalis E., Mastrokalou C., Urbanova M., Matuskova M., Demkova L., Medova V., Longhin E.M., Rundén-Pran E., Dusinska M., Rios-Mondragon I., Cimpan M.R., Gabelova A., Soltysova A., Smolkova B., Chatziioannou A. Decitabine-induced DNA methylationmediated transcriptomic reprogramming in human breast cancer cell lines; the impact of DCK overexpression. Front Pharmacol. 2022; 13. doi: 10.3389/fphar.2022.991751.

Champion C., Guianvarc’h D., Sénamaud-Beaufort C., Jurkowska R.Z., Jeltsch A., Ponger L., Arimondo P.B., Guieysse-Peugeot A.L. Mechanistic insights on the inhibition of c5 DNA methyltransferases by zebularine. PLoS One. 2010; 5(8). doi: 10.1371/journal.pone.0012388.

Lu Y., Chan Y.T., Tan H.Y., Li S., Wang N., Feng Y. Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy. Mol Cancer. 2020; 19(1): 79. doi: 10.1186/s12943-020-01197-3.

Cheng J.C., Yoo C.B., Weisenberger D.J., Chuang J., Wozniak C., Liang G., Marquez V.E., Greer S., Orntoft T.F., Thykjaer T., Jones P.A. Preferential response of cancer cells to zebularine. Cancer Cell. 2004; 6(2): 151–8. doi: 10.1016/j.ccr.2004.06.023.

Takemura Y., Satoh M., Hatanaka K., Kubota S. Zebularine exerts its antiproliferative activity through S phase delay and cell death in human malignant mesothelioma cells. Biosci Biotechnol Biochem. 2018; 82(7): 1159–64. doi: 10.1080/09168451.2018.1459466.

Cheng J.C., Weisenberger D.J., Gonzales F.A., Liang G., Xu G.L., Hu Y.G., Marquez V.E., Jones P.A. Continuous zebularine treatment effectively sustains demethylation in human bladder cancer cells. Mol Cell Biol. 2004; 24(3): 1270–8. doi: 10.1128/MCB.24.3.1270-1278.2004.

Lemaire M., Momparler L.F., Raynal N.J., Bernstein M.L., Momparler R.L. Inhibition of cytidine deaminase by zebularine enhances the antineoplastic action of 5-aza-2'-deoxycytidine. Cancer Chemother Pharmacol. 2009; 63(3): 411–6. doi: 10.1007/s00280-008-0750-6.

Fulkerson C.M., Dhawan D., Jones D.R., Marquez V.E., Jones P.A., Wang Z., Wu Q., Klaunig J.E., Fourez L.M., Bonney P.L., Knapp D.W. Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs. Vet Comp Oncol. 2017; 15(1): 226–36. doi: 10.1111/vco.12159.

Holleran J.L., Eiseman J.L., Parise R.A., Kummar S., Beumer J.H. LC-MS/MS assay for the quantitation of FdCyd and its metabolites FdUrd and FU in human plasma. J Pharm Biomed Anal. 2016; 129: 359–66. doi: 10.1016/j.jpba.2016.07.027.

Guo D., Myrdal P.B., Karlage K.L., O’Connell S.P., Wissinger T.J., Tabibi S.E., Yalkowsky S.H. Stability of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in combination. AAPS PharmSciTech. 2010; 11(1): 247–52. doi: 10.1208/s12249-010-9383-2.

Holleran J.L., Beumer J.H., McCormick D.L., Johnson W.D., Newman E.M., Doroshow J.H., Kummar S., Covey J.M., Davis M., Eiseman J.L. Oral and intravenous pharmacokinetics of 5-fluoro-2'-deoxycytidine and THU in cynomolgus monkeys and humans. Cancer Chemother Pharmacol. 2015; 76(4): 803–11. doi: 10.1007/s00280-015-2857-x.

Coyne G.O.', Wang L., Zlott J., Juwara L., Covey J.M., Beumer J.H., Cristea M.C., Newman E.M., Koehler S., Nieva J.J., Garcia A.A., Gandara D.R.,Miller B., Khin S., Miller S.B., Steinberg S.M., Rubinstein L., Parchment R.E., Kinders R.J., Piekarz R.L., Kummar S., Chen A.P., Doroshow J.H. Intravenous 5-fluoro-2’-deoxycytidine administered with tetrahydrouridine increases the proportion of p16-expressing circulating tumor cells in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2020; 85(5): 979–93. doi: 10.1007/s00280-020-04073-5.

Brueckner B., Rius M., Markelova M.R., Fichtner I., Hals P.A., Sandvold M.L., Lyko F. Delivery of 5-azacytidine to human cancer cells by elaidic acid esterification increases therapeutic drug efficacy. Mol Cancer Ther. 2010; 9(5): 1256–64. doi: 10.1158/1535-7163.MCT-09-1202.

Rius M., Stresemann C., Keller D., Brom M., Schirrmacher E., Keppler D., Lyko F. Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation. Mol Cancer Ther. 2009; 8(1): 225–31. doi: 10.1158/1535-7163.MCT-08-0743.

Byun H.M., Choi S.H., Laird P.W., Trinh B., Siddiqui M.A., Marquez V.E., Yang A.S. 2'-Deoxy-N4-[2-(4-nitrophenyl)ethoxycarbonyl]-5 -azacytidine: a novel inhibitor of DNA methyltransferase that requires activation by human carboxylesterase 1. Cancer Lett. 2008; 266(2): 238–48. doi: 10.1016/j.canlet.2008.02.069.

Srivastava P., Paluch B.E., Matsuzaki J., James S.R., CollamatLai G., Karbach J., Nemeth M.J., Taverna P., Karpf A.R., Griffiths E.A. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts. Leuk Res. 2014; 38(11): 1332–41. doi: 10.1016/j.leukres.2014.09.001.

Garcia-Manero G., Roboz G., Walsh K., Kantarjian H., Ritchie E., Kropf P., O’Connell C., Tibes R., Lunin S., Rosenblat T., Yee K., Stock W., Griffiths E., Mace J., Podoltsev N., Berdeja J., Jabbour E., Issa J.J., Hao Y., Keer H.N., Azab M., Savona M.R. Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: phase 2 results from a multicentre, open-label, randomised, phase 1/2 trial. Lancet Haematol. 2019; 6(6): 317–27. doi: 10.1016/S2352-3026(19)30029-8.

Oza A.M., Matulonis U.A., Secord A.A., Nemunaitis J., Roman L.D., Blagden S.P., Banerjee S., McGuire W.P., Ghamande S., Birrer M.J., Fleming G.F., Markham M.J., Hirte H.W., Provencher D.M., Basu B., Kristeleit R., Armstrong D.K., Schwartz B., Braly P., Hall G.D., Nephew K.P., Jueliger S., Oganesian A., Naim S., Hao Y., Keer H., Azab M., Matei D. A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer. Clin Cancer Res. 2020; 26(5): 1009–16. doi: 10.1158/1078-0432.CCR-19-1638.

Chen S., Xie P., Cowan M., Huang H., Cardenas H., Keathley R., Tanner E.J., Fleming G.F., Moroney J.W., Pant A., Akasha A.M., Davuluri R.V., Kocherginsky M., Zhang B., Matei D. Epigenetic priming enhances antitumor immunity in platinum-resistant ovarian cancer. J Clin Invest. 2022; 132(14). doi: 10.1172/JCI158800.

Crabb S.J., Danson S., Catto J.W.F., Hussain S., Chan D., Dunkley D., Downs N., Marwood E., Day L., Saunders G., Light M., Whitehead A., Ellis D., Sarwar N., Enting D., Birtle A., Johnson B., Huddart R., Griffiths G. Phase I Trial of DNA Methyltransferase Inhibitor Guadecitabine Combined with Cisplatin and Gemcitabine for Solid Malignancies Including Urothelial Carcinoma (SPIRE). Clin Cancer Res. 2021; 27(7): 1882–92. doi: 10.1158/1078-0432.CCR-20-3946.

Brueckner B., Lyko F. DNA methyltransferase inhibitors: old and new drugs for an epigenetic cancer therapy. Trends Pharmacol Sci. 2004; 25(11): 551–4. doi: 10.1016/j.tips.2004.09.004.

Ou Y., Zhang Q., Tang Y., Lu Z., Lu X., Zhou X., Liu C. DNA methylation enzyme inhibitor RG108 suppresses the radioresistance of esophageal cancer. Oncol Rep. 2018; 39(3): 993–1002. doi: 10.3892/or.2018.6210.

Yang L., Hou J., Cui X.H., Suo L.N., Lv Y.W. RG108 induces the apoptosis of endometrial cancer Ishikawa cell lines by inhibiting the expression of DNMT3B and demethylation of HMLH1. Eur Rev Med Pharmacol Sci. 2017; 21(22): 5056–64. doi: 10.26355/eurrev_201711_13818.

Lee B.H., Yegnasubramanian S., Lin X., Nelson W.G. Procainamide is a specific inhibitor of DNA methyltransferase 1. J Biol Chem. 2005; 280(49): 40749–56. doi: 10.1074/jbc.M505593200.

Villar-Garea A., Fraga M.F., Espada J., Esteller M. Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. Cancer Res. 2003; 63(16): 4984–9.

Sabit H., Samy M.B., Said O.A., El-Zawahri M.M. Procaine Induces Epigenetic Changes in HCT116 Colon Cancer Cells. Genet Res Int. 2016. doi: 10.1155/2016/8348450.

Li Y.C., Wang Y., Li D.D., Zhang Y., Zhao T.C., Li C.F. Procaine is a specific DNA methylation inhibitor with anti-tumor effect for human gastric cancer. J Cell Biochem. 2018; 119(2): 2440–9. doi: 10.1002/jcb.26407.

Ma X.W., Li Y., Han X.C., Xin Q.Z. The effect of low dosage of procaine on lung cancer cell proliferation. Eur Rev Med Pharmacol Sci. 2016; 20(22): 4791–5.

Gao Z., Xu Z., Hung M.S., Lin Y.C., Wang T., Gong M., Zhi X., Jablons D.M., You L. Procaine and procainamide inhibit the Wnt canonical pathway by promoter demethylation of WIF-1 in lung cancer cells. Oncol Rep. 2009; 22(6): 1479–84. doi: 10.3892/or_00000590.

Uetrecht J.P., Freeman R.W., Woosley R.L. The implications of procainamide metabolism to its induction of lupus. Arthritis Rheum. 1981; 24(8): 994–1003. doi: 10.1002/art.1780240803.

Paşa S., Erdogan O., Cevik O. Design, synthesis and investigation of procaine based new Pd complexes as DNA methyltransferase inhibitor on gastric cancer cells. Inorg Chem Comm. 2021; 132. doi: 10.1016/j.inoche.2021.108846.

Tanaka H., Marumo H., Nagai T., Okada M., Taniguchi K. Nanaomycins, new antibiotics produced by a strain of Streptomyces. III. A new component, nanaomycin C, and biological activities of nanaomycin derivatives. J Antibiot (Tokyo). 1975; 28(12): 925–30. doi: 10.7164/antibiotics.28.925.

Kormanec J., Novakova R., Csolleiova D., Feckova L., Rezuchova B., Sevcikova B., Homerova D. The antitumor antibiotic mithramycin: new advanced approaches in modification and production. Appl Microbiol Biotechnol. 2020; 104(18): 7701–21. doi: 10.1007/s00253-020-10782-x.

Kuck D., Caulfield T., Lyko F., Medina-Franco J.L. Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells. Mol Cancer Ther. 2010; 9(11): 3015–23. doi: 10.1158/1535-7163.MCT-10-0609.

Liu P.Y., Sokolowski N., Guo S.T., Siddiqi F., Atmadibrata B., Telfer T.J., Sun Y., Zhang L., Yu D., Mccarroll J., Liu B., Yang R.H., Guo X.Y., Tee A.E., Itoh K., Wang J., Kavallaris M., Haber M., Norris M.D., Cheung B.B., Byrne J.A., Ziegler D.S., Marshall G.M., Dinger M.E., Codd R., Zhang X.D., Liu T. The BET bromodomain inhibitor exerts the most potent synergistic anticancer effects with quinone-containing compounds and anti-microtubule drugs. Oncotarget. 2016; 7(48): 79217–32. doi: 10.18632/oncotarget.12640.

Lin R.K., Hsu C.H., Wang Y.C. Mithramycin A inhibits DNA methyltransferase and metastasis potential of lung cancer cells. Anticancer Drugs. 2007; 18(10): 1157–64. doi: 10.1097/CAD.0b013e3282a215e9.

Arce C., Segura-Pacheco B., Perez-Cardenas E., Taja-Chayeb L., Candelaria M., Dueñnas-Gonzalez A. Hydralazine target: from blood vessels to the epigenome. J Transl Med. 2006; 4: 10. doi: 10.1186/1479-5876-4-10.

Graça I., Sousa E.J., Costa-Pinheiro P., Vieira F.Q., TorresFerreira J., Martins M.G., Henrique R., Jerónimo C. Anti-neoplastic properties of hydralazine in prostate cancer. Oncotarget. 2014; 5(15): 5950–64. doi: 10.18632/oncotarget.1909.

Singh N., Dueñas-González A., Lyko F., Medina-Franco J.L. Molecular modeling and molecular dynamics studies of hydralazine with human DNA methyltransferase 1. ChemMedChem. 2009; 4(5): 792–9. doi: 10.1002/cmdc.200900017.

Kumanishi S., Yamanegi K., Nishiura H., Fujihara Y., Kobayashi K., Nakasho K., Futani H., Yoshiya S. Epigenetic modulators hydralazine and sodium valproate act synergistically in VEGI-mediated anti-angiogenesis and VEGF interference in human osteosarcoma and vascular endothelial cells. Int J Oncol. 2019; 55(1): 167–78. doi: 10.3892/ijo.2019.4811.

Bauman J., Shaheen M., Verschraegen C.F., Belinsky S.A., Houman Fekrazad M., Lee F.C., Rabinowitz I., Ravindranathan M., Jones D.V. Jr. A Phase I Protocol of Hydralazine and Valproic Acid in Advanced, Previously Treated Solid Cancers. Transl Oncol. 2014; 7(3): 349–54. doi: 10.1016/j.tranon.2014.03.001.

Espinoza-Zamora J.R., Labardini-Méndez J., Sosa-Espinoza A., López-González C., Vieyra-García M., Candelaria M., Lozano-Zavaleta V., Toledano-Cuevas D.V., Zapata-Canto N., Cervera E., Dueñas-González A. Efficacy of hydralazine and valproate in cutaneous T-cell lymphoma, a phase II study. Expert Opin Investig Drugs. 2017; 26(4): 481–7. doi: 10.1080/13543784.2017.1291630. Erratum in: Expert Opin Investig Drugs. 2017; 26(4): 523. doi: 10.1080/13543784.2017.1306178.

Maiti A., Daver N.G. Eprenetapopt in the Post-Transplant Setting: Mechanisms and Future Directions. J Clin Oncol. 2022; 40(34): 3994–7. doi: 10.1200/JCO.22.01505.

Qiang W., Jin T., Yang Q., Liu W., Liu S., Ji M., He N., Chen C., Shi B., Hou P. PRIMA-1 selectively induces global DNA demethylation in p53 mutant-type thyroid cancer cells. J Biomed Nanotechnol. 2014; 10(7): 1249–58. doi: 10.1166/jbn.2014.1862.

Teoh P.J., Bi C., Sintosebastian C., Tay L.S., Fonseca R., Chng W.J. PRIMA-1 targets the vulnerability of multiple myeloma of deregulated protein homeostasis through the perturbation of ER stress via p73 demethylation. Oncotarget. 2016; 7(38): 61806–19. doi: 10.18632/oncotarget.11241.

Fujihara K.M., Zhang B.Z., Jackson T.D., Ogunkola M.O., Nijagal B., Milne J.V., Sallman D.A., Ang C.S., Nikolic I., Kearney C.J., Hogg S.J., Cabalag C.S., Sutton V.R., Watt S., Fujihara A.T., Trapani J.A., Simpson K.J., Stojanovski D., Leimkühler S., Haupt S., Phillips W.A., Clemons N.J. Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction. Sci Adv. 2022; 8(37). doi: 10.1126/sciadv.abm9427.

Amirtharaj F., Venkatesh G.H., Wojtas B., Nawafleh H.H., Mahmood A.S., Nizami Z.N., Khan M.S., Thiery J., Chouaib S. p53 reactivating small molecule PRIMA-1MET/APR-246 regulates genomic instability in MDA-MB-231 cells. Oncol Rep. 2022; 47(4): 85. doi: 10.3892/or.2022.8296.

Fransson Å., Glaessgen D., Alfredsson J., Wiman K.G., BajalicaLagercrantz S., Mohell N. Strong synergy with APR-246 and DNAdamaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer. J Ovarian Res. 2016; 9(1): 27. doi: 10.1186/s13048-016-0239-6.

Sallman D.A., Dezern A.E., Steensma D., Sweet K.L., Cluzeau T., Sekeres M., Garcia-Manero G., Roboz G.J., McLemore A.F., McGraw K.L., Puskas J., Zhang L., Bhagat C.K., Yao J., Ali N.A., Padron E., Tell R., Lancet J.E., Fenaux P., List A., Komrokji R.S. Phase 1b/2 Combination Study of APR-246 and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML). Blood Adv. 2018; 132 (s1). doi: 10.1182/blood-2018-99-119990.

Sun N., Zhang J., Zhang C., Zhao B., Jiao A. DNMTs inhibitor SGI-1027 induces apoptosis in Huh7 human hepatocellular carcinoma cells. Oncol Lett. 2018; 16(5): 5799–806. doi: 10.3892/ol.2018.9390.

García-Domínguez P., Dell'aversana C., Alvarez R., Altucci L., de Lera A.R. Synthetic approaches to DNMT inhibitor SGI-1027 and effects on the U937 leukemia cell line. Bioorg Med Chem Lett. 2013; 23(6): 1631–5. doi: 10.1016/j.bmcl.2013.01.085.

Kelly G.S. Quercetin. Monograph. Altern Med Rev. 2011; 16(2): 172–94.

Билык О.В., Рыбальченко В.К., Романюк Б.П. Биофлавоноид кверцетин и перспективы его использования в медицине. Загальна патология та патологiчна фiзiологiя. 2007; 2(1): 4–9.

Bilyk O.V., Rybalchenko V.K., Romanyuk B.P. Bioflavonoid quercetin and the prospects for its use in medicine. General pathology and pathological physiology. 2007; 2(1): 4–9. (in Russian).

Alvarez M.C., Maso V., Torello C.O., Ferro K.P., Saad S.T.O. The polyphenol quercetin induces cell death in leukemia by targeting epigenetic regulators of pro-apoptotic genes. Clin Epigenetics. 2018; 10(1): 139. doi: 10.1186/s13148-018-0563-3.

Kedhari Sundaram M., Hussain A., Haque S., Raina R., Afroze N. Quercetin modifies 5’CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells. J Cell Biochem. 2019; 120(10): 18357–69. doi: 10.1002/jcb.29147.

Almatroodi S.A., Almatroudi A., Khan A.A., Alhumaydhi F.A., Alsahli M.A., Rahmani A.H. Potential Therapeutic Targets of Epigallocatechin Gallate (EGCG), the Most Abundant Catechin in Green Tea, and Its Role in the Therapy of Various Types of Cancer. Molecules. 2020; 25(14): 3146. doi: 10.3390/molecules25143146.

Minnelli C., Cianfruglia L., Laudadio E., Mobbili G., Galeazzi R., Armeni T. Effect of Epigallocatechin-3-Gallate on EGFR Signaling and Migration in Non-Small Cell Lung Cancer. Int J Mol Sci. 2021; 22(21). doi: 10.3390/ijms222111833.

Della Via F.I., Shiraishi R.N., Santos I., Ferro K.P., SalazarTerreros M.J., Franchi Junior G.C., Rego E.M., Saad S.T.O., Torello C.O. (-)-Epigallocatechin-3-gallate induces apoptosis and differentiation in leukaemia by targeting reactive oxygen species and PIN1. Sci Rep. 2021; 11(1). doi: 10.1038/s41598-021-88478-z.

Sheng J., Shi W., Guo H., Long W., Wang Y., Qi J., Liu J., Xu Y. The Inhibitory Effect of (-)-Epigallocatechin-3-Gallate on Breast Cancer Progression via Reducing SCUBE2 Methylation and DNMT Activity. Molecules. 2019; 24(16). doi: 10.3390/molecules24162899.

Khan M.A., Hussain A., Sundaram M.K., Alalami U., Gunasekera D., Ramesh L., Hamza A., Quraishi U. (-)-Epigallocatechin-3-gallate reverses the expression of various tumor-suppressor genes by inhibiting DNA methyltransferases and histone deacetylases in human cervical cancer cells. Oncol Rep. 2015; 33(4): 1976–84. doi: 10.3892/or.2015.3802.

Nandakumar V., Vaid M., Katiyar S.K. (-)-Epigallocatechin3-gallate reactivates silenced tumor suppressor genes, Cip1/p21 and p16INK4a, by reducing DNA methylation and increasing histones acetylation in human skin cancer cells. Carcinogenesis. 2011; 32(4): 537–44. doi: 10.1093/carcin/bgq285.

Alizadeh M., Nafari A., Safarzadeh A., Veiskarami S., Almasian M., Asghar Kiani A. The Impact of EGCG and RG108 on SOCS1 Promoter DNA Methylation and Expression in U937 Leukemia Cells. Rep Biochem Mol Biol. 2021; 10(3): 455–61. doi: 10.52547/rbmb.10.3.455.

Khan M.I., Nur S.M., Abdulaal W.H. A study on DNA methylation modifying natural compounds identified EGCG for induction of IFI16 gene expression related to the innate immune response in cancer cells. Oncol Lett. 2022; 24(1): 218. doi: 10.3892/ol.2022.13339.

Fang M.Z., Wang Y., Ai N., Hou Z., Sun Y., Lu H., Welsh W., Yang C.S. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 2003; 63(22): 7563–70.

Chen L.L., Han W.F., Geng Y., Su J.S. A genome-wide study of DNA methylation modified by epigallocatechin-3-gallate in the CAL-27 cell line. Mol Med Rep. 2015; 12(4): 5886–90. doi: 10.3892/mmr.2015.4118.

McLarty J., Bigelow R.L., Smith M., Elmajian D., Ankem M., Cardelli J.A. Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro. Cancer Prev Res (Phila). 2009; 2(7): 673–82. doi: 10.1158/1940-6207.CAPR-08-0167.

Jazvinšćak Jembrek M., Oršolić N., Mandić L., Sadžak A., Šegota S. Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-κB and p53 Pathways in Neurodegeneration. Antioxidants (Basel). 2021; 10(10). doi: 10.3390/antiox10101628.

Jia S., Xu X., Zhou S., Chen Y., Ding G., Cao L. Fisetin induces autophagy in pancreatic cancer cells via endoplasmic reticulum stress- and mitochondrial stress-dependent pathways. Cell Death Dis. 2019; 10(2). doi: 10.1038/s41419-019-1366-y. Erratum in: Cell Death Dis. 2024; 15(1). doi: 10.1038/s41419-023-06399-3.

Mukhtar E., Adhami V.M., Sechi M., Mukhtar H. Dietary flavonoid fisetin binds to β-tubulin and disrupts microtubule dynamics in prostate cancer cells. Cancer Lett. 2015; 367(2): 173–83. doi: 10.1016/j.canlet.2015.07.030.

Hassan F.U., Rehman M.S., Khan M.S., Ali M.A., Javed A., Nawaz A., Yang C. Curcumin as an Alternative Epigenetic Modulator: Mechanism of Action and Potential Effects. Front Genet. 2019; 10. doi: 10.3389/fgene.2019.00514.

Кирсанов К.И., Власова О.А., Фетисов Т.И., Зенков Р.Г., Лесовая Е.А., Белицкий Г.А., Гурова К., Якубовская М.Г. Влияние ДНКтропных антиканцерогенных соединений на механизмы регуляции экспрессии генов. Успехи молекулярной онкологии. 2018; 5(4): 41–63. doi: 10.17650/2313-805X-2018-5-4-41-63.

Kirsanov K.I., Vlasova O.A., Fetisov T.I., Zenkov R.G., Lesovaya E.A., Belitsky G.A., Gurova K., Yakubovskaya M.G. Influence of DNA-binding compounds with cancer preventive activity on the mechanisms of gene expression regulation. Advances in Molecular Oncology. 2018; 5(4): 41–63. (in Russian). doi: 10.17650/2313-805X-2018-5-4-41-63.

Yu J., Peng Y., Wu L.C., Xie Z., Deng Y., Hughes T., He S., Mo X., Chiu M., Wang Q.E., He X., Liu S., Grever M.R., Chan K.K., Liu Z. Curcumin down-regulates DNA methyltransferase 1 and plays an anti-leukemic role in acute myeloid leukemia. PLoS One. 2013; 8(2). doi: 10.1371/ journal.pone.0055934.

Chen J., Ying Y., Zhu H., Zhu T., Qu C., Jiang J., Fang B. Curcumininduced promoter hypermethylation of the mammalian target of rapamycin gene in multiple myeloma cells. Oncol Lett. 2019; 17(1): 1108–14. doi: 10.3892/ol.2018.9662.

Al-Yousef N., Shinwari Z., Al-Shahrani B., Al-Showimi M., AlMoghrabi N. Curcumin induces re-expression of BRCA1 and suppression of γ synuclein by modulating DNA promoter methylation in breast cancer cell lines. Oncol Rep. 2020; 43(3): 827–38. doi: 10.3892/or.2020.7473.

Link A., Balaguer F., Shen Y., Lozano J.J., Leung H.C., Boland C.R., Goel A. Curcumin modulates DNA methylation in colorectal cancer cells. PLoS One. 2013; 8(2). doi: 10.1371/journal.pone.0057709.

Hosokawa M., Seiki R., Iwakawa S., Ogawara K.I. Combination of azacytidine and curcumin is a potential alternative in decitabineresistant colorectal cancer cells with attenuated deoxycytidine kinase. Biochem Biophys Res Commun. 2021; 578: 157–62. doi: 10.1016/j.bbrc.2021.09.041.

100

Howells L.M., Iwuji C.O.O., Irving G.R.B., Barber S., Walter H., Sidat Z., Griffin-Teall N., Singh R., Foreman N., Patel S.R., Morgan B., Steward W.P., Gescher A., Thomas A.L., Brown K. Curcumin Combined with FOLFOX Chemotherapy Is Safe and Tolerable in Patients with Metastatic Colorectal Cancer in a Randomized Phase IIa Trial. J Nutr. 2019; 149(7): 1133–9. doi: 10.1093/jn/nxz029.

101

Saghatelyan T., Tananyan A., Janoyan N., Tadevosyan A., Petrosyan H., Hovhannisyan A., Hayrapetyan L., Arustamyan M., Arnhold J., Rotmann A.R., Hovhannisyan A., Panossian A. Efficacy and safety of curcumin in combination with paclitaxel in patients with advanced, metastatic breast cancer: A comparative, randomized, double-blind, placebo-controlled clinical trial. Phytomedicine. 2020; 70. doi: 10.1016/j.phymed.2020.153218.

102

Rauf A., Imran M., Suleria H.A.R., Ahmad B., Peters D.G., Mubarak M.S. A comprehensive review of the health perspectives of resveratrol. Food Funct. 2017; 8(12): 4284–305. doi: 10.1039/c7fo01300k.

103

Aldawsari F.S., Aguayo-Ortiz R., Kapilashrami K., Yoo J., Luo M., Medina-Franco J.L., Velázquez-Martínez C.A. Resveratrolsalicylate derivatives as selective DNMT3 inhibitors and anticancer agents. J Enzyme Inhib Med Chem. 2016; 31(5): 695–703. doi: 10.3109/14756366.2015.1058256.

104

Izquierdo-Torres E., Hernández-Oliveras A., Meneses-Morales I., Rodríguez G., Fuentes-García G., Zarain-Herzberg Á. Resveratrol upregulates ATP2A3 gene expression in breast cancer cell lines through epigenetic mechanisms. Int J Biochem Cell Biol. 2019; 113: 37–47. doi: 10.1016/j.biocel.2019.05.020.

105

Sharifi-Rad J., Quispe C., Imran M., Rauf A., Nadeem M., Gondal T.A., Ahmad B., Atif M., Mubarak M.S., Sytar O., Zhilina O.M., Garsiya E.R., Smeriglio A., Trombetta D., Pons D.G., Martorell M., Cardoso S.M., Razis A.F.A., Sunusi U., Kamal R.M., Rotariu L.S., Butnariu M., Docea A.O., Calina D. Genistein: An Integrative Overview of Its Mode of Action, Pharmacological Properties, and Health Benefits. Oxid Med Cell Longev. 2021. doi: 10.1155/2021/3268136.

106

Sundaram M.K., Ansari M.Z., Al Mutery A., Ashraf M., Nasab R., Rai S., Rais N., Hussain A. Genistein Induces Alterations of Epigenetic Modulatory Signatures in Human Cervical Cancer Cells. Anticancer Agents Med Chem. 2018; 18(3): 412–21. doi: 10.2174/1871520617666170918142114.

107

Sharma M., Tollefsbol T.O. Combinatorial epigenetic mechanisms of sulforaphane, genistein and sodium butyrate in breast cancer inhibition. Exp Cell Res. 2022; 416(1). doi: 10.1016/j.yexcr.2022.113160.

108

Xie Q., Bai Q., Zou L.Y., Zhang Q.Y., Zhou Y., Chang H., Yi L., Zhu J.D., Mi M.T. Genistein inhibits DNA methylation and increases expression of tumor suppressor genes in human breast cancer cells. Genes Chromosomes Cancer. 2014; 53(5): 422–31. doi: 10.1002/gcc.22154.

109

Romagnolo D.F., Donovan M.G., Papoutsis A.J., Doetschman T.C., Selmin O.I. Genistein Prevents BRCA1 CpG Methylation and Proliferation in Human Breast Cancer Cells with Activated Aromatic Hydrocarbon Receptor. Curr Dev Nutr. 2017; 1(6). doi: 10.3945/cdn.117.000562.

110

Li H., Xu W., Huang Y., Huang X., Xu L., Lv Z. Genistein demethylates the promoter of CHD5 and inhibits neuroblastoma growth in vivo. Int J Mol Med. 2012; 30(5): 1081–6. doi: 10.3892/ijmm.2012.1118.

111

Pintova S., Dharmupari S., Moshier E., Zubizarreta N., Ang C., Holcombe R.F. Genistein combined with FOLFOX or FOLFOX-Bevacizumab for the treatment of metastatic colorectal cancer: phase I/II pilot study. Cancer Chemother Pharmacol. 2019; 84(3): 591–8. doi: 10.1007/s00280-019-03886-3.

112

Chua G.N.L., Wassarman K.L., Sun H., Alp J.A., Jarczyk E.I., Kuzio N.J., Bennett M.J., Malachowsky B.G., Kruse M., Kennedy A.J. Cytosine-Based TET Enzyme Inhibitors. ACS Med Chem Lett. 2019; 10(2): 180–5. doi: 10.1021/acsmedchemlett.8b00474.

113

Weirath N.A., Hurben A.K., Chao C., Pujari S.S., Cheng T., Liu S., Tretyakova N.Y. Small Molecule Inhibitors of TET Dioxygenases: Bobcat339 Activity Is Mediated by Contaminating Copper(II). ACS Med Chem Lett. 2022; 13(5): 792–8. doi: 10.1021/acsmedchemlett.1c00677.

114

Singh A.K., Zhao B., Liu X., Wang X., Li H., Qin H., Wu X., Ma Yu., Horne D., Yu X. Selective targeting of TET catalytic domain promotes somatic cell reprogramming. Proc Natl Acad Sci U S A. 2020; 117(7): 3621–6. doi: 10.1073/pnas.1910702117.

115

Guan Y., Tiwari A.D., Phillips J.G., Hasipek M., Grabowski D.R., Pagliuca S., Gopal P., Kerr C.M., Adema V., Radivoyevitch T., Parker Y., Lindner D.J., Meggendorfer M., Abazeed M., Sekeres M.A., Mian O.Y., Haferlach T., Maciejewski J.P., Jha B.K. A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms. Blood Cancer Discov. 2021; 2(2): 146–61. doi: 10.1158/2643-3230.BCD-20-0173.

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