oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2018-17-3-77-87oncotomsk-768Research ArticleОБЗОРЫREVIEWSВАРИАНТЫ И ПЕРСПЕКТИВЫ ПЕРЕПРОФИЛИРОВАНИЯ ЛЕКАРСТВЕННЫХ ПРЕПАРАТОВ ДЛЯ ИСПОЛЬЗОВАНИЯ В ТЕРАПИИ ОНКОЛОГИЧЕСКИХ ЗАБОЛЕВАНИЙVARIANTS AND PERSPECTIVES OF DRUG REPURPOSING FOR CANCER TREATMENTСавинковаА. В.SavinkovaA. V.

115478, г. Москва, Каширское шоссе, 24

младший научный сотрудник отдела химического канцерогенеза, ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» (г. Москва, Россия). SPIN-код (РИНЦ): 9805-7127.  Researcher ID (WOS): K-6838-2018. Author ID (Scopus): 985189

24, Kashirskoe shosse, 115478-Moscow,Russia

Junior Researcher, Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology (Moscow, Russia).  Researcher ID (WOS): K-6838-2018. Author ID (Scopus): 985189

alenka.savinkova@mail.ruЖидковаЕ. М.ZhidkovaE. M.

115478, г. Москва, Каширское шоссе, 24

младший научный сотрудник отдела химического канцерогенеза, ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» (г. Москва, Россия)

24, Kashirskoe shosse, 115478-Moscow,Russia

Junior Researcher, Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology (Moscow, Russia)

Zhidkova_EM@mail.ruТиловаЛ. Р.TilovaL. R.

115478, г. Москва, Каширское шоссе, 24

аспирант отдела химического канцерогенеза ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» (г. Москва, Россия)

24, Kashirskoe shosse, 115478-Moscow,Russia

Postgraduate, Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology (Moscow, Russia)

uhtishkachik@mail.ruЛавроваМ. Д.LavrovaM. D.

125047, г. Москва, Миусская площадь, 9

студент, Российский химико-технологический университет им. Д.И. Менделеева (г. Москва, Россия)

9, Miusskaya sq., 125047-Moscow, Russia

Student, D.I. Mendeleev University of Chemical Technology of Russia (Moscow, Russia)

mahoony@mail.ruЛыловаЕ. С.LylovaE. S.

119454, г. Москва, пр. Вернадского, 78

студент, Московский технологический университет (г. Москва, Россия)

78, Vernadsky Avenue, Moscow-119454, Russia

Student, Moscow Technological University (Moscow, Russia)

e.s.lylova@gmail.comКузинК. А.KuzinK. A.

115478, г. Москва, Каширское шоссе, 24

младший научный сотрудник отдела химического канцерогенеза, ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» (г. Москва, Россия)

24, Kashirskoe shosse, 115478-Moscow,Russia

Junior Researcher, Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology (Moscow, Russia)

kuzin_konstantin@mail.ruПортянниковаА. Ю.PortyannikovaA. Yu.

115478, г. Москва, Каширское шоссе, 24

лаборант-исследователь отдела химического канцерогенеза ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» (г. Москва, Россия)

24, Kashirskoe shosse, 115478-Moscow,Russia

Laboratory Research Assistant, Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology (Moscow, Russia)

lesovenok@yandex.ruМаксимоваВ. П.MaximovaV. P.

115478, г. Москва, Каширское шоссе, 24

младший научный сотрудник отдела химического канцерогенеза ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» (г. Москва, Россия)

24, Kashirskoe shosse, 115478-Moscow,Russia

Junior Researcher, Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology (Moscow, Russia)

lavarvar@gmail.comХолодоваА. В.KholodovaA. V.

119454, г. Москва, пр. Вернадского, 78

студент, Московский технологический университет (г. Москва, Россия)

78, Vernadsky Avenue, Moscow-119454, Russia

Student, Moscow Technological University (Moscow, Russia)

kholodova.alyona@yandex.ruВласоваО. А.VlasovaO. A.

115478, г. Москва, Каширское шоссе, 24

младший научный сотрудник отдела химического канцерогенеза, ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» (г. Москва, Россия)

24, Kashirskoe shosse, 115478-Moscow,Russia

Junior Researcher, Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology (Moscow, Russia)

olya_vlasov@mail.ruФетисовТ. И.FetisovT. I.

115478, г. Москва, Каширское шоссе, 24

лаборант-исследователь отдела химического канцерогенеза ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» (г. Москва, Россия). SPIN-код (РИНЦ): 6890-8393. Author ID (Scopus): 974443

24, Kashirskoe shosse, 115478-Moscow,Russia

Laboratory Research Assistant, Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology (Moscow, Russia)

timkatryam@yandex.ruhttps://orcid.org/0000-0002-8599-6833КирсановК. И.KirsanovK. I.

115478, г. Москва, Каширское шоссе, 24

кандидат биологических наук, заведующий лабораторией канцерогенных веществ отдела химического канцерогенеза, ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» (г. Москва, Россия). SPIN-код (РИНЦ): 7329-7263. Researcher ID (WOS): L-3062-2015. Author ID (Scopus): 184421

24, Kashirskoe shosse, 115478-Moscow,Russia

PhD, Head of Laboratory of Chemical Carcinogens, N.N. Blokhin National Medical Research Center of Oncology (Moscow, Russia). Researcher ID (WOS): L-3062-2015. Author ID (Scopus): 184421

kkirsanov85@yandex.ruБелицкийГ. А.BelitskiyG. A.

115478, г. Москва, Каширское шоссе, 24

доктор медицинских наук, профессор, ведущий научный сотрудник отдела химического канцерогенеза, ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» (г.  Москва, Россия). SPIN-код (РИНЦ): 4037-0033. Researcher ID (WOS): L-3062-2015. Author ID (Scopus): 107231

24, Kashirskoe shosse, 115478-Moscow,Russia

MD, PhD, DSc, Professor, Leading Researcher, Department of Chemical Carcinogenesis N.N. Blokhin National Medical Research Center of Oncology (Moscow, Russia). Researcher ID (WOS): L-3062-2015. Author ID (Scopus): 107231

belitsga@mail.ruhttps://orcid.org/0000-0002-9710-8178ЯкубовскаяМ. Г.YakubovskayaM. G.

115478, г. Москва, Каширское шоссе, 24

доктор медицинских наук, заведующая отделом химического канцерогенеза, ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» (г. Москва, Россия).  SPIN-код (РИНЦ): 6858-3880. Researcher ID (WOS): R-6984-2016. Author ID (Scopus): 583045

24, Kashirskoe shosse, 115478-Moscow,Russia

MD, PhD, DSc, Head of Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology (Moscow, Russia). Researcher ID (WOS): R-6984-2016. Author ID (Scopus): 583045

mgyakubovskaya@mail.ruhttps://orcid.org/0000-0002-1967-9637ЛесоваяЕ. А.LesovayaE. A.

115478, г. Москва, Каширское шоссе, 24

390026, г. Рязань, ул. Высоковольтная, 9

кандидат биологических наук, старший научный сотрудник отдела химического канцерогенеза ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» (г.  Москва, Россия). SPIN-код (РИНЦ): 7593-2167. Researcher ID (WOS): J-7790-2015. Author ID (Scopus): 583044

24, Kashirskoe shosse, 115478-Moscow,Russia

9, Vysokovoltnaya Str., 390026-Ryazan, Russia

PhD, Senior Researcher, Department of Chemical Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology (Moscow, Russia). Researcher ID (WOS): J-7790-2015. Author ID (Scopus): 583044

lesovenok@yandex.ruФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава РоссииРоссияN.N. Blokhin National Medical Research Center of OncologyRussian FederationФГБОУ ВО «Российский химико-технологический университет им. Д.И. Менделеева»РоссияD.I. Mendeleev University of Chemical Technology of RussiaRussian FederationФГБОУ ВО «Московский технологический университет»РоссияMoscow Technological UniversityRussian FederationФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России ФГБОУ ВО «Рязанский государственный медицинский университет имени академика И.П. Павлова» Минздрава РоссииРоссияN.N. Blokhin National Medical Research Center of Oncology I.P. Pavlov Ryazan State Medical UniversityRussian Federation2018040720181737787Copyright © Савинкова А.В., Жидкова Е.М., Тилова Л.Р., Лаврова М.Д., Лылова Е.С., Кузин К.А., Портянникова А.Ю., Максимова В.П., Холодова А.В., Власова О.А., Фетисов Т.И., Кирсанов К.И., Белицкий Г.А., Якубовская М.Г., Лесовая Е.А., 20182018Савинкова А.В., Жидкова Е.М., Тилова Л.Р., Лаврова М.Д., Лылова Е.С., Кузин К.А., Портянникова А.Ю., Максимова В.П., Холодова А.В., Власова О.А., Фетисов Т.И., Кирсанов К.И., Белицкий Г.А., Якубовская М.Г., Лесовая Е.А.Savinkova A.V., Zhidkova E.M., Tilova L.R., Lavrova M.D., Lylova E.S., Kuzin K.A., Portyannikova A.Y., Maximova V.P., Kholodova A.V., Vlasova O.A., Fetisov T.I., Kirsanov K.I., Belitskiy G.A., Yakubovskaya M.G., Lesovaya E.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/768

В настоящее время появились новые программы по перепрофилированию или перепозиционированию лекарственных средств, используемых в медицинской практике.  Перепрофилирование препаратов позволяет не только использовать отработанные схемы  синтеза биологически активных соединений, но и избежать проведения исследований,  необходимых для внедрения новых лекарственных препаратов в медицинскую практику, по  фармакокинетике, канцерогенности, острой и хронической токсичности, в том числе  кардиотоксичности, нефротоксичности, аллергенности и т.д. Это создает возможность сократить объем необходимых исследований и снизить затраты на них. В онкологии  программы перепрофилирования лекарственных средств включают как поиск препаратов,  обладающих противоопухолевой активностью или потенцирующих действие  противоопухолевых препаратов, среди известных и широко применяемых лекарственных  средств, используемых для лечения неонкологических заболеваний, так и анализ  возможности использования уже известных противоопухолевых препаратов для лечения  каких-либо новых нозологических форм заболевания. Основанием для поиска  противоопухолевых свойств среди препаратов иного назначения является тот факт, что  сигнальные пути в клетке характеризуются большим количеством перекрестных  взаимодействий и некоторые из них могут ингибировать пролиферацию опухолевых клеток.  Современные достижения геномики, протеомики, биоинформатики, появление объемных баз данных по молекулярным эффектам лекарственных препаратов, мощных аналитических систем и их постоянное совершенствование уже позволяет исследователям  одновременно проанализировать большое количество существующих препаратов в  применении к конкретной молекулярной мишени. В обзоре рассмотрены основные подходы  и ресурсы, использующиеся в настоящее время для перепрофилирования лекарственных  препаратов, а также приведен ряд примеров.

Recently many new approaches for repurposing or repositioning of the clinically used drugs have been developed. Drug repurposing  allows not only to use known schemes for the synthesis of  biologically active compounds, but also to avoid multiple studies that  are necessary for drug approval process – analysis of  pharmacokinetics, carcinogenicity, acute and chronic toxicity,  including cardiotoxicity, nephrotoxicity, allergenicity etc. It makes  possible to reduce the number of experimental studies as well as  costs of investigations. In cancer research drug repurposing includes screening for medicines used nowadays for the treatment of patients with non-cancer diseases which possess anticancer activity or able to enhance the effects of the standard anticancer chemotherapy, and  search for new applications of known anticancer drugs for the  treatment of different cancer types. Scientific rationale for the search of the compounds with potential anticancer properties among drugs  with different applications is based on the multiple cross-talks of  signaling pathways, which can inhibit cell proliferation. Modern  advances in genomics, proteomics and bioinformatics, development  of permanently improving databases of drug molecular effects and  high throughput analytical systems allow researchers to analyze  simultaneously a large bulk of existing drugs and specific molecular targets. This review describes the main approaches and  resources currently used for the drug repurposing, as well as a  number of examples.

перепрофилирование лекарственных препаратовонкологиябазы данных по эффектам ксенобиотиковметоды перепрофилированияdrug repurposingcancerdatabases on xenobiotics’ effectsrepurposing approachesReferencesGupta S.C., Sung B., Prasad S., Webb L.J., Aggarwal B.B. Cancer drug discovery by repurposing: teaching new tricks to old dogs. Trends Pharmacol Sci. 2013 Sep; 34 (9): 508–17. doi: 10.1016/j.tips.2013.06.005.Gupta S.C., Sung B., Prasad S., Webb L.J., Aggarwal B.B. Cancer drug discovery by repurposing: teaching new tricks to old dogs. Trends Pharmacol Sci. 2013 Sep; 34 (9): 508–17. doi: 10.1016/j.tips.2013.06.005.GSM GROUP. Аналитический отчет. Фармацевтический рынок России. Итоги 2016 г. 2016; 100.GSM GROUP. Analytical report. Pharmaceutical market in Russia. Results of 2016. 2016; 100. [in Russian]Rotella D.P. Drug discovery 2012 and beyond. ACS Med Chem Lett. 2012 Jan 31; 3 (3): 172–3. doi: 10.1021/ml300022p.Rotella D.P. Drug discovery 2012 and beyond. ACS Med Chem Lett. 2012 Jan 31; 3 (3): 172–3. doi: 10.1021/ml300022p.Гервас П.А., Литвяков Н.В., Попова Н.О., Добродеев А.Ю., Тарасова А.С., Юмов Е.Л., Иванова Ф.Г., Черемисина О.В., Афанасьев С.Г., Гольдберг В.Е., Чердынцева Н.В. Проблемы и перспективы совершенствования молекулярно-генетической диагностики для назначения таргетных препаратов в онкологии. Сибирский онкологический журнал. 2014; 2: 46–55.Gervas P.A., Litviakov N.V., Popova N.O., Dobrodeev A.Yu., Tarasova A.S., Yumov E.L., Ivanova F.G., Cheremisina O.V., Afanasyev S.G., Goldberg V.E., Cherdyntseva N.V. Problem and perspective to improve molecular testing to choose appropriate target therapy. Siberian Journal of Oncology. 2014; 2: 46–55. [in Russian]Jin G., Wong S.T. Toward better drug repositioning: prioritizing and integrating existing methods into efficient pipelines. Drug Discov Today. 2014 May; 19 (5): 63744. doi: 10.1016/j.drudis.2013.11.005.Jin G., Wong S.T. Toward better drug repositioning: prioritizing and integrating existing methods into efficient pipelines. Drug Discov Today. 2014 May; 19 (5): 63744. doi: 10.1016/j.drudis.2013.11.005.Pfister D.G. Off-label use of oncology drugs: the need for more data and then some. J Clin Oncol. 2012; 30 (6): 584–6. doi: 10.1200/JCO.2011.38.5567.Pfister D.G. Off-label use of oncology drugs: the need for more data and then some. J Clin Oncol. 2012; 30 (6): 584–6. doi: 10.1200/JCO.2011.38.5567.Swamidass S.J. Mining small-molecule screens to repurpose drugs. Brief Bioinform. 2011 Jul; 12 (4): 327–35. doi: 10.1093/bib/bbr028.Swamidass S.J. Mining small-molecule screens to repurpose drugs. Brief Bioinform. 2011 Jul; 12 (4): 327–35. doi: 10.1093/bib/bbr028.Jin G., Fu C., Zhao H., Cui K., Chang J., Wong S.T. A novel method of transcriptional response analysis to facilitate drug repositioning for cancer therapy. Cancer Res. 2012 Jan 1; 72 (1): 33–44. doi: 10.1158/0008-5472.CAN-11-2333.Jin G., Fu C., Zhao H., Cui K., Chang J., Wong S.T. A novel method of transcriptional response analysis to facilitate drug repositioning for cancer therapy. Cancer Res. 2012 Jan 1; 72 (1): 33–44. doi: 10.1158/0008-5472.CAN-11-2333.McCabe B., Liberante F., Mills K.I. Repurposing medicinal compounds for blood cancer treatment. Ann Hematol. 2015 Aug; 94 (8): 1267–76. doi: 10.1007/s00277-015-2412-1.McCabe B., Liberante F., Mills K.I. Repurposing medicinal compounds for blood cancer treatment. Ann Hematol. 2015 Aug; 94 (8): 1267–76. doi: 10.1007/s00277-015-2412-1.Fu C., Jin G., Gao J., Zhu R., Ballesteros-Villagrana E., Wong S.T. DrugMap Central: an on- line query and visualization tool to facilitate drug repositioning studies. Bioinformatics. 2013 Jul 15; 29 (14): 1834–6. doi: 10.1093/bioinformatics/btt279.Fu C., Jin G., Gao J., Zhu R., Ballesteros-Villagrana E., Wong S.T. DrugMap Central: an on-line query and visualization tool to facilitate drug repositioning studies. Bioinformatics. 2013 Jul 15; 29 (14): 1834–6. doi: 10.1093/bioinformatics/btt279.Zhao H., Jin G., Cui K., Ren D., Liu T., Chen P., Wong S., Li F., Fan Y., Rodriguez A., Chang J., Wong S.T. Novel modeling of cancer cell signaling pathways enables systematic drug repositioning for distinct breast cancer metastases. Cancer Res. 2013 Oct 15; 73 (20): 6149– 63. doi: 10.1158/0008-5472.CAN-12-4617.Zhao H., Jin G., Cui K., Ren D., Liu T., Chen P., Wong S., Li F., Fan Y., Rodriguez A., Chang J., Wong S.T. Novel modeling of cancer cell signaling pathways enables systematic drug repositioning for distinct breast cancer metastases. Cancer Res. 2013 Oct 15; 73 (20): 6149–63. doi: 10.1158/0008-5472.CAN-12-4617.Houghton P.J., Morton C.L., Gorlick R., Lock R.B., Carol H., Reynolds C.P., Kang M.H., Maris J.M., Keir S.T., Kolb E.A., Wu J., Wozniak A.W., Billups C.A., Rubinstein L., Smith M.A. Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Mol Cancer Ther. 2010 Jan; 9 (1): 10112. doi: 10.1158/1535-7163. MCT-09-0952.Houghton P.J., Morton C.L., Gorlick R., Lock R.B., Carol H., Reynolds C.P., Kang M.H., Maris J.M., Keir S.T., Kolb E.A., Wu J., Wozniak A.W., Billups C.A., Rubinstein L., Smith M.A. Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Mol Cancer Ther. 2010 Jan; 9 (1): 10112. doi: 10.1158/1535-7163.MCT-09-0952.Blatt J. Corey S.J. Drug repurposing in pediatrics and pediatric hematology oncology. Drug Discov Today. 2013 Jan; 18 (1–2): 4–10. doi: 10.1016/j.drudis.2012.07.009.Blatt J. Corey S.J. Drug repurposing in pediatrics and pediatric hematology oncology. Drug Discov Today. 2013 Jan; 18 (1–2): 4–10. doi: 10.1016/j.drudis.2012.07.009.Sirota M., Dudley J.T., Kim J., Chiang A.P., Morgan A.A., Sweet-Cordero A., Sage J., Butte A.J. Discovery and preclinical validation of drug indications using compendia of public gene expression data. SSci Transl Med. 2011 Aug 17; 3 (96): 96ra77. doi: 10.1126/scitranslmed.3001318.Sirota M., Dudley J.T., Kim J., Chiang A.P., Morgan A.A., Sweet- Cordero A., Sage J., Butte A.J. Discovery and preclinical validation of drug indications using compendia of public gene expression data. SSci Transl Med. 2011 Aug 17; 3 (96): 96ra77. doi: 10.1126/scitranslmed.3001318.Chen X., Yan C.C., Zhang X., Zhang X., Dai F., Yin J., Zhang Y. Drug-target interaction prediction: databases, web servers and computational models. Brief Bioinform. 2016 Jul; 17 (4): 696–712. doi: 10.1093/bib/bbv066.Chen X., Yan C.C., Zhang X., Zhang X., Dai F., Yin J., Zhang Y. Drug-target interaction prediction: databases, web servers and computational models. Brief Bioinform. 2016 Jul; 17 (4): 696–712. doi: 10.1093/bib/bbv066.Liu Z., Fang H., Reagan K., Xu X., Mendrick D.L., Slikker W., Jr., Tong W. In silico drug repositioning: what we need to know. Drug Discov Today. 2013 Feb; 18 (3–4): 110–5. doi: 10.1016/j.drudis.2012.08.005.Liu Z., Fang H., Reagan K., Xu X., Mendrick D.L., Slikker W., Jr., Tong W. In silico drug repositioning: what we need to know. Drug Discov Today. 2013 Feb; 18 (3–4): 110–5. doi: 10.1016/j.drudis.2012.08.005.Wu Z., Wang Y., Chen L. Network-based drug repositioning. Mol Biosyst. 2013 Jun; 9 (6): 1268–81. doi: 10.1039/c3mb25382a.Wu Z., Wang Y., Chen L. Network-based drug repositioning. Mol Biosyst. 2013 Jun; 9 (6): 1268–81. doi: 10.1039/c3mb25382a.Cheng F., Hong H., Yang S., Wei Y. Individualized network-based drug repositioning infrastructure for precision oncology in the panomics era. Brief Bioinform. 2017 Jul 1; 18 (4): 682–697. doi: 10.1093/bib/bbw051.Cheng F., Hong H., Yang S., Wei Y. Individualized network-based drug repositioning infrastructure for precision oncology in the panomics era. Brief Bioinform. 2017 Jul 1; 18 (4): 682–697. doi: 10.1093/bib/bbw051.Pritchard J.E., O’Mara T.A., Glubb D.M. Enhancing the Promise of Drug Repositioning through Genetics. Front Pharmacol. 2017 Dec 6; 8: 896. doi: 10.3389/fphar.2017.00896.Pritchard J.E., O’Mara T.A., Glubb D.M. Enhancing the Promise of Drug Repositioning through Genetics. Front Pharmacol. 2017 Dec 6; 8: 896. doi: 10.3389/fphar.2017.00896.Lamb J., Crawford E.D., Peck D., Modell J.W., Blat I.C., Wrobel M.J., Lerner J., Brunet J.P., Subramanian A., Ross K.N., Reich M., Hieronymus H., Wei G., Armstrong S.A., Haggarty S.J., Clemons P.A., Wei R., Carr S.A., Lander E.S., Golub T.R. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006; 313 (5795): 1929–35.Lamb J., Crawford E.D., Peck D., Modell J.W., Blat I.C., Wrobel M.J., Lerner J., Brunet J.P., Subramanian A., Ross K.N., Reich M., Hieronymus H., Wei G., Armstrong S.A., Haggarty S.J., Clemons P.A., Wei R., Carr S.A., Lander E.S., Golub T.R. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006; 313 (5795): 1929–35.Duan Q., Flynn C., Niepel M., Hafner M., Muhlich J.L., Fernandez N.F., Rouillard A.D., Tan C.M., Chen E.Y., Golub T.R., Sorger P.K., Subramanian A., Ma’ayan A. LINCS Canvas Browser: interactive web app to query, browse and interrogate LINCS L1000 gene expression signatures. Nucleic Acids Res. 2014 Jul; 42 (Web Server issue): W449–60. doi: 10.1093/nar/gku476.Duan Q., Flynn C., Niepel M., Hafner M., Muhlich J.L., Fernandez N.F., Rouillard A.D., Tan C.M., Chen E.Y., Golub T.R., Sorger P.K., Subramanian A., Ma’ayan A. LINCS Canvas Browser: interactive web app to query, browse and interrogate LINCS L1000 gene expression signatures. Nucleic Acids Res. 2014 Jul; 42 (Web Server issue): W449–60. doi: 10.1093/nar/gku476.Корман Д. Перепрофилирование лекарств для онкологии. Практическая онкология, 2017; 18 (1): 139–158.Korman D. Drug repurposing in oncology. Practical Oncology. 2017; 18 (1): 139–158. [in Russian]Набережнов Д., Глазунов В., Лесовая Е., Белицкий Г., Якубовская М., Кирсанов К. Сравнительный анализ влияния узкобороздочных лигандов на активацию белка PARP1. Современные проблемы науки и образования. 2016 (6): 134–134.Naberezhnov D., Glazunov V., Lesovaya E., Belitsky G., Yakubovskaya M., Kirsanov K. Influence of minor groove binding ligands on PARP1 activation: comparative analysis. Modern Problems of Science and Education. 2016; 6: 134–134. [in Russian]Kirsanov K.I., Kotova E., Makhov P., Golovine K., Lesovaya E.A., Kolenko V.M., Yakubovskaya M.G., Tulin A.V. Minor grove binding ligands disrupt PARP-1 activation pathways. Oncotarget. 2014; 5 (2): 428–37.Kirsanov K.I., Kotova E., Makhov P., Golovine K., Lesovaya E.A., Kolenko V.M., Yakubovskaya M.G., Tulin A.V. Minor grove binding ligands disrupt PARP-1 activation pathways. Oncotarget. 2014; 5 (2): 428–37.Zhou J., Le V., Kalia D., Nakayama S., Mikek C., Lewis E.A., Sintim H.O. Diminazene or berenil, a classic duplex minor groove binder, binds to G-quadruplexes with low nanomolar dissociation constants and the amidine groups are also critical for G-quadruplex binding. Mol Biosyst. 2014; 10 (10): 2724–34.Zhou J., Le V., Kalia D., Nakayama S., Mikek C., Lewis E.A., Sintim H.O. Diminazene or berenil, a classic duplex minor groove binder, binds to G-quadruplexes with low nanomolar dissociation constants and the amidine groups are also critical for G-quadruplex binding. Mol Biosyst. 2014; 10 (10): 2724–34.Wang C., Carter-Cooper B., Du Y., Zhou J., Saeed M.A., Liu J., Guo M., Roembke B., Mikek C., Lewis E.A., Lapidus R.G., and Sintim H.O. Alkyne-substituted diminazene as G-quadruplex binders with anticancer activities. Eur J Med Chem. 2016 Aug 8; 118: 266–75. doi: 10.1016/j.ejmech.2016.04.030.Wang C., Carter-Cooper B., Du Y., Zhou J., Saeed M.A., Liu J., Guo M., Roembke B., Mikek C., Lewis E.A., Lapidus R.G., and Sintim H.O. Alkyne-substituted diminazene as G-quadruplex binders with anticancer activities. Eur J Med Chem. 2016 Aug 8; 118: 266–75. doi: 10.1016/j.ejmech.2016.04.030.Gegotek A., Cyunczyk M., Luczaj W., Bielawska A., Bielawski K., Skrzydlewska E. The redox status of human breast cancer cell lines (MCF-7 and MDA-MB231) treated with novel dinuclear berenil-platinum(II) complexes. Pharmazie. 2014; 69 (12): 923–8.Gegotek A., Cyunczyk M., Luczaj W., Bielawska A., Bielawski K., Skrzydlewska E. The redox status of human breast cancer cell lines (MCF-7 and MDA-MB231) treated with novel dinuclear berenil-platinum(II) complexes. Pharmazie. 2014; 69 (12): 923–8.Jarocka I., Gegotek A., Bielawska A., Bielawski K., Luczaj W., Hodun T., Skrzydlewska E. Effect of novel dinuclear platinum(II) complexes on redox status of MOLT-4 leukemic cells. Toxicol Mech Methods. 2013 Nov; 23 (9): 641–9. doi: 10.3109/15376516.2013.825359.Jarocka I., Gegotek A., Bielawska A., Bielawski K., Luczaj W., Hodun T., Skrzydlewska E. Effect of novel dinuclear platinum(II) complexes on redox status of MOLT-4 leukemic cells. Toxicol Mech Methods. 2013 Nov; 23 (9): 641–9. doi: 10.3109/15376516.2013.825359.Bielawski K., Czarnomysy R., Muszynska A., Bielawska A., Poplawska B. Cytotoxicity and induction of apoptosis of human breast cancer cells by novel platinum(II) complexes. Environ Toxicol Pharmacol. 2013 Mar; 35 (2): 254–64. doi: 10.1016/j.etap.2012.12.010.Bielawski K., Czarnomysy R., Muszynska A., Bielawska A., Poplawska B. Cytotoxicity and induction of apoptosis of human breast cancer cells by novel platinum(II) complexes. Environ Toxicol Pharmacol. 2013 Mar; 35 (2): 254–64. doi: 10.1016/j.etap.2012.12.010.Czarnomysy R., Bielawska A., Muszynska A., Bielawski K. Effects of novel alkyl pyridine platinum complexes on apoptosis in Ishikawa endometrial cancer cells. Med Chem. 2015; 11 (6): 540–50.Czarnomysy R., Bielawska A., Muszynska A., Bielawski K. Effects of novel alkyl pyridine platinum complexes on apoptosis in Ishikawa endometrial cancer cells. Med Chem. 2015; 11 (6): 540–50.Gornowicz A., Bielawska A., Szymanowski W., Gabryel-Porowska H., Czarnomysy R., Bielawski K. Mechanism of anticancer action of novel berenil complex of platinum(II) combined with anti-MUC1 in MCF-7 breast cancer cells. Oncol Lett. 2018 Feb; 15 (2): 2340– 2348. doi: 10.3892/ol.2017.7623.Gornowicz A., Bielawska A., Szymanowski W., Gabryel-Porowska H., Czarnomysy R., Bielawski K. Mechanism of anticancer action of novel berenil complex of platinum(II) combined with anti-MUC1 in MCF-7 breast cancer cells. Oncol Lett. 2018 Feb; 15 (2): 2340–2348. doi: 10.3892/ol.2017.7623.Lesovaya E., Agarwal S., Readhead B., Vinokour E., Baida G., Bhalla P., Kirsanov K., Yakubovskaya M., Platanias L.C., Dudley J.T., Budunova I. Rapamycin modulates glucocorticoid receptor function, blocks atrophogene REDD1, and protects skin from steroid atrophy. J Invest Dermatol. 2018 Mar 26. pii: S0022-202X(18)31809-8. doi: 10.1016/j.jid.2018.02.045.Lesovaya E., Agarwal S., Readhead B., Vinokour E., Baida G., Bhalla P., Kirsanov K., Yakubovskaya M., Platanias L.C., Dudley J.T., Budunova I. Rapamycin modulates glucocorticoid receptor function, blocks atrophogene REDD1, and protects skin from steroid atrophy. J Invest Dermatol. 2018 Mar 26. pii: S0022-202X(18)31809-8. doi: 10.1016/j.jid.2018.02.045.Baida G., Bhalla P., Kirsanov K., Lesovaya E., Yakubovskaya M., Yuen K., Guo S., Lavker R.M., Readhead B., Dudley J.T., Budunova I. REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids. EMBO Mol Med. 2015 Jan; 7 (1): 42–58. doi: 10.15252/emmm.201404601.Baida G., Bhalla P., Kirsanov K., Lesovaya E., Yakubovskaya M., Yuen K., Guo S., Lavker R.M., Readhead B., Dudley J.T., Budunova I. REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids. EMBO Mol Med. 2015 Jan; 7 (1): 42–58. doi: 10.15252/emmm.201404601.Fischkoff S.A., Walter E.Jr. Induction of neutrophilic differentiation of human promyelocytic leukemic cells by branched-chain carboxylic acid anticonvulsant drugs. J Biol Response Mod. 1984; 3 (2): 132–7.Fischkoff S.A., Walter E.Jr. Induction of neutrophilic differentiation of human promyelocytic leukemic cells by branched-chain carboxylic acid anticonvulsant drugs. J Biol Response Mod. 1984; 3 (2): 132–7.Gu S., Tian Y., Chlenski A., Salwen H.R., Lu Z., Raj J.U., Yang Q. Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma. Anticancer Drugs. 2012; 23 (10): 1054–66.Gu S., Tian Y., Chlenski A., Salwen H.R., Lu Z., Raj J.U., Yang Q. Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma. Anticancer Drugs. 2012; 23 (10): 1054–66.Michaelis M., Doerr H.W., Cinatl J.Jr. Valproic acid as anti-cancer drug. Curr Pharm Des. 2007; 13 (33): 3378–93.Michaelis M., Doerr H.W., Cinatl J.Jr. Valproic acid as anti-cancer drug. Curr Pharm Des. 2007; 13 (33): 3378–93.Leaute-Labreze C., Dumas de la Roque E., Hubiche T., Boralevi F., Thambo J.B., Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008 Jun 12; 358 (24): 2649–51. doi: 10.1056/NEJMc0708819.Leaute-Labreze C., Dumas de la Roque E., Hubiche T., Boralevi F., Thambo J.B., Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008 Jun 12; 358 (24): 2649–51. doi: 10.1056/NEJMc0708819.Zhang L., Mai H.M., Zheng J., Zheng J.W., Wang Y.A., Qin Z.P., and Li K.L. Propranolol inhibits angiogenesis via down-regulating the expression of vascular endothelial growth factor in hemangioma derived stem cell. Int J Clin Exp Pathol. 2014; 7 (1): 48–55.Zhang L., Mai H.M., Zheng J., Zheng J.W., Wang Y.A., Qin Z.P., and Li K.L. Propranolol inhibits angiogenesis via down-regulating the expression of vascular endothelial growth factor in hemangioma derived stem cell. Int J Clin Exp Pathol. 2014; 7 (1): 48–55.Greenberger S., Bischoff J. Infantile hemangioma-mechanism(s) of drug action on a vascular tumor. Cold Spring Harb Perspect Med. 2011; 1 (1): a006460.Greenberger S., Bischoff J. Infantile hemangioma-mechanism(s) of drug action on a vascular tumor. Cold Spring Harb Perspect Med. 2011; 1 (1): a006460.Kuang X., Qi M., Peng C., Zhou C., Su J., Zeng W., Liu H., Zhang J., Chen M., Shen M., Xie X., Li F., Zhao S., Li Q., Luo Z., Chen J., Tao J., He Y., Chen X. Propranolol enhanced the anti- tumor effect of sunitinib by inhibiting proliferation and inducing G0/G1/S phase arrest in malignant melanoma. Oncotarget. 2017 Nov 25; 9 (1): 802–811. doi: 10.18632/oncotarget.22696.Kuang X., Qi M., Peng C., Zhou C., Su J., Zeng W., Liu H., Zhang J., Chen M., Shen M., Xie X., Li F., Zhao S., Li Q., Luo Z., Chen J., Tao J., He Y., Chen X. Propranolol enhanced the anti-tumor effect of sunitinib by inhibiting proliferation and inducing G0/G1/S phase arrest in malignant melanoma. Oncotarget. 2017 Nov 25; 9 (1): 802–811. doi: 10.18632/oncotarget.22696.Montoya A., Amaya C.N., Belmont A., Diab N., Trevino R., Villanueva G., Rains S., Sanchez L.A., Badri N., Otoukesh S., Khammanivong A., Liss D., Baca S.T., Aguilera R.J., Dickerson E.B., Torabi A., Dwivedi A.K., Abbas A., Chambers K., Bryan B.A., Nahleh Z. Use of non-selective beta-blockers is associated with decreased tumor proliferative indices in early stage breast cancer. Oncotarget. 2017 Jan 24; 8 (4): 6446–6460. doi: 10.18632/oncotarget.14119.Montoya A., Amaya C.N., Belmont A., Diab N., Trevino R., Villanueva G., Rains S., Sanchez L.A., Badri N., Otoukesh S., Khammanivong A., Liss D., Baca S.T., Aguilera R.J., Dickerson E.B., Torabi A., Dwivedi A.K., Abbas A., Chambers K., Bryan B.A., Nahleh Z. Use of non-selective beta-blockers is associated with decreased tumor proliferative indices in early stage breast cancer. Oncotarget. 2017 Jan 24; 8 (4): 6446–6460. doi: 10.18632/oncotarget.14119.Wang F., Liu H., Wang F., Xu R., Wang P., Tang F., Zhang X., Zhu Z., Lv H., and Han T. Propranolol suppresses the proliferation and induces the apoptosis of liver cancer cells. Mol Med Rep. 2018 Apr; 17 (4): 5213–5221. doi: 10.3892/mmr.2018.8476.Wang F., Liu H., Wang F., Xu R., Wang P., Tang F., Zhang X., Zhu Z., Lv H., and Han T. Propranolol suppresses the proliferation and induces the apoptosis of liver cancer cells. Mol Med Rep. 2018 Apr; 17 (4): 5213–5221. doi: 10.3892/mmr.2018.8476.Jang H.I., Lim S.H., Lee Y.Y., Kim T.J., Choi C.H., Lee J.W., Kim B.G., Bae D.S. Perioperative administration of propranolol to women undergoing ovarian cancer surgery: A pilot study. Obstet Gynecol Sci. 2017 Mar; 60 (2): 170–177. doi: 10.5468/ogs.2017.60.2.170.Jang H.I., Lim S.H., Lee Y.Y., Kim T.J., Choi C.H., Lee J.W., Kim B.G., Bae D.S. Perioperative administration of propranolol to women undergoing ovarian cancer surgery: A pilot study. Obstet Gynecol Sci. 2017 Mar; 60 (2): 170–177. doi: 10.5468/ogs.2017.60.2.170.Stenvang J., Kumler I., Nygard S.B., Smith D.H., Nielsen D., Brunner N., Moreira J.M. Biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy: a novel strategy in drug development. Front Oncol. 2013 Dec 25; 3: 313. doi: 10.3389/fonc.2013.00313.Stenvang J., Kumler I., Nygard S.B., Smith D.H., Nielsen D., Brunner N., Moreira J.M. Biomarker-guided repurposing of chemotherapeutic drugs for cancer therapy: a novel strategy in drug development. Front Oncol. 2013 Dec 25; 3: 313. doi: 10.3389/fonc.2013.00313.Horisberger K., Erben P., Muessle B., Woernle C., Stroebel P., Kaehler G., Wenz F., Hochhaus A., Post S., Willeke F., Hofheinz R.D.; MARGIT (Mannheimer Arbeitsgruppe für Gastrointestinale Tumoren). I expression correlates to response to neoadjuvant irinotecan- based chemoradiation in rectal cancer. Anticancer Drugs. 2009 Jul; 20 (6): 519–24. doi: 10.1097/CAD.0b013e32832b53ff.Horisberger K., Erben P., Muessle B., Woernle C., Stroebel P., Kaehler G., Wenz F., Hochhaus A., Post S., Willeke F., Hofheinz R.D.; MARGIT (Mannheimer Arbeitsgruppe für Gastrointestinale Tumoren). I expression correlates to response to neoadjuvant irinotecan-based chemoradiation in rectal cancer. Anticancer Drugs. 2009 Jul; 20 (6): 519–24. doi: 10.1097/CAD.0b013e32832b53ff.Lan H., Li Y., Lin C.Y. Irinotecan as a palliative therapy for metastatic breast cancer patients after previous chemotherapy. Asian Pac J Cancer Prev. 2014; 15 (24): 10745–8.Lan H., Li Y., Lin C.Y. Irinotecan as a palliative therapy for metastatic breast cancer patients after previous chemotherapy. Asian Pac J Cancer Prev. 2014; 15 (24): 10745–8.Kumler I., Brunner N., Stenvang J., Balslev E., Nielsen D.L. A systematic review on topoisomerase 1 inhibition in the treatment of metastatic breast cancer. Breast Cancer Res Treat. 2013 Apr; 138 (2): 347–58. doi: 10.1007/s10549-013-2476-3.Kumler I., Brunner N., Stenvang J., Balslev E., Nielsen D.L. A systematic review on topoisomerase 1 inhibition in the treatment of metastatic breast cancer. Breast Cancer Res Treat. 2013 Apr; 138 (2): 347–58. doi: 10.1007/s10549-013-2476-3.

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