COMPARATIVE STUDY OF ECHINOCHROME A, OXYGENATED CAROTENOIDS, GINSENOSIDE Rh2, LUTEOLIN DISULFATE AND METFORMIN AS A MEAN TO POTENTIATE ANTITUMOR EFFECT OF DOXORUBICIN

This work concerned a comparative study of potentiating effects produced by some drugs of natural origin, as well as metformin, upon antitumor activity of doxorubicin. An increased therapeutic efficacy of doxorubicin used in combination with echinochrome A, oxycarotenoids, ginsenoside Rh2, and metformin was tested in the in vivo Ehrlich ascites carcinoma model. The negative effect of luteolin disulfate (10 mg/kg body weight) upon efficacy of antitumor therapy was revealed. When studying the effect of these substances on the level of intracellular ROS in primary cultures of murine spleen cells, using a selective fluorescent indicator (2’,7’-dichlorofluorescein-diacetate), we did not find a positive correlation between induction of excessive ROS synthesis and potentiation of doxorubicin action with the compounds studied. Some of the studied agents showed a positive correlation between interferon-inducing activity, as well as a negative correlation between increased IL-1 content, and higher antitumor effect of doxorubicin. The obtained results suggest expedience of further studies of antitumor effect potentiation using preparations of echinochrome, ginsenoside Rh2, a mixture of oxygenated carotenoids and metformin.

1. Калинина Е.В., Чернов Н.Н., Новичкова М.Д. Роль глутатиона, глутатионтрансферазы и глутаредоксина в регуляции редокс-зависимых процессов // Успехи биологической химии, 2014. Т. 54. С. 299-348. [Kalinina E.V., Chernov N.N., Novichkova M.D. Role of glutathione, glutathione transferase, and glutaredoxin in regulation of redox-dependent processes. Uspekhi biologicheskoy khimii = Advances in Biochemistry, 2014, Vol. 54, pp. 299-348. (In Russ.)]

2. Крылова Н.В., Попов А.М., Леонова Г.Н. Антиоксиданты как потенциальные антивирусные агенты при флавивирусных инфекциях // Антибиотики и химиотерапия, 2016. Т. 61, № 5-6. С. 25-31. [Krylova N.V., Popov A.M., Leonova G.N. Antioxidants as potential antiviral agents for flavivirus infections. Antibiotiki i khimioterapiya = Antibiotiсs and Chemotherapy, 2016, Vol. 61, no. 5-6, pp. 25-31. (In Russ.)]

3. Попов А.М. Противоопухолевая и антиметастатическая активность моноглюкозидов женьшеня: современные представления // Биофармацевтический журнал, 2011. Т. 3, № 5. С. 3-8. [Popov A.M. Antineoplastic and antimetastatic activity of ginseng monoglycosides: modern concepts. Biofarmatsevticheskiy zhurnal = Biopharmaceutical Journal, 2011, Vol. 3, no. 5, pp. 3-8. (In Russ.)]

4. Попов А.М., Кривошапко О.Н., Артюков А.А. Сравнительная оценка фармакологической активности лютелина и 7,3’-дисульфата лютеолина при моделировании разных патологий // Биофармацевтический журнал, 2011. Т. 3. № 4. С. 27-33. [Popov A.M., Krivoshapko O.N., Artyukov A.A. The comparative evaluation of the pharmacological activity of lutelein and lutelin 7,3’-disulfate in the modeling of various pathologies. Biofarmatsevticheskiy zhurnal = Biopharmaceutical Journal, 2011, Vol. 3, no. 4, pp. 27-33. (In Russ.)]

5. Попов А.М., Кривошапко О.Н., Артюков А.А. Механизмы протективной фармакологической активности флавоноидов // Биофармацевтический журнал, 2012. Т. 4, № 4. С. 27-41. [Popov A.M., Krivoshapko O.N., Artyukov A.A. Mechanisms of protective pharmacological activity of flavonoids. Biofarmatsevticheskiy zhurnal = Biopharmaceutical Journal, 2012, Vol. 4, no. 4, pp. 27-41. (In Russ.)]

6. Попов А.М., Кривошапко О.Н., Артюков А.А. Перспективы клинического применения астаксантина и других оксигенированных каротиноидов // Биофармацевтический журнал, 2013. Т. 5, № 5. С. 13-30. [Popov A.M., Krivoshapko O.N., Artyukov A.A. Prospects for the clinical use of astaxanthin and other oxygenated carotenoids. Biofarmatsevticheskiy zhurnal = Biopharmaceutical Journal, 2013, Vol. 5, no. 5, pp. 13-30. (In Russ.)]

7. Попов А.М., Кривошапко О.Н., Цыбульский А.В., Штода Ю.П., Климович А.А., Шнайдер К.Д., Артюков А.А. Оценка лечебной активности различных природных соединений при моделировании аллергического контактного дерматита // Биофармацевтический журнал, 2014. Т. 6, № 5. С. 3-10. [Popov A.M., Krivoshapko O.N., Tsybulsky A.V., Shtoda Yu.P., Klimovich A.A., Schneider K.D., Artyukov A.A. Evaluation of the therapeutic activity of various natural compounds in the modeling of allergic contact dermatitis. Biofarmatsevticheskiy zhurnal = Biopharmaceutical Journal, 2014, Vol. 6, no. 5, pp. 3-10. (In Russ.)]

8. Попов А.М., Кривошапко О.Н., Артюков А.А. Механизмы протективного действия эхинохрома А при различных патологиях // Биофармацевтический журнал, 2016. Т. 8, № 4. С. 7-13. [Popov A.M., Krivoshapko O.N., Artyukov A.A. Mechanisms of the protective effect of echinochrome A for various pathologies. Biofarmatsevticheskiy zhurnal = Biopharmaceutical Journal, 2016, Vol. 8, no. 4, pp. 7-13. (In Russ.)]

9. Попов А.М., Осипов А.Н., Корепанова Е.А., Кривошапко О.Н., Артюков А.А., Климович А.А. Изучение антиоксидантной и мембранной активности эхинохрома А с использованием различных модельных систем // Биофизика, 2017. Т. 62, № 3. С. 509-517. [Popov A.M., Osipov A.N., Korepanova E.A., Krivoshapko O.N., Artyukov A.A., Klimovich A.A. The study of antioxidant and membrane activity of echinochrome A using various model systems. Biofizika = Biophysics, 2017, Vol. 62, no. 3, pp. 509-517. (In Russ.)]

10. Разина Т.Г., Крылова С.Г., Амосова Е.Н., Зуева Е.П., Лопатина К.А., Попов А.М., Атопкина Л.Н., Козловская Э.П. Влияние гинзенозида Rh2 на развитие перевиваемых опухолей животных и эффективность химиотерапии // Экспериментальная и клиническая фармакология, 2010. Т. 73, № 4. С. 27-30. [Razina T.G., Krylova S.G., Amosova E.N., Zueva E.P., Lopatina K.A., Popov A.M., Atopkina L.N., Kozlovskaya E.P. The influence of ginsenoside Rh2 on the development of transplanted animal tumors and the effectiveness of chemotherapy. Eksperimentalnaya i klinicheskaya farmakologiya = Experimental and Clinical Pharmacology, 2010, Vol. 73, no. 4, pp. 27-30. (In Russ.)]

11. Саенко Ю.В., Шутов А.М. Изучение генотоксических свойств доксорубицина с использованием клеточной модели Saccharomyces cerevisiae // Экспериментальная и клиническая фармакология, 2007. Т. 70, № 3. С. 29-32. [Saenko Yu.V., Shutov A.M. The study of the genotoxic properties of doxorubicin using the Saccharomyces cerevisiae cell model. Eksperimentalnaya i klinicheskaya farmakologiya = Experimental and Clinical Pharmacology, 2007, Vol. 70, no. 3, pp. 29-32. (In Russ.)]

12. Цыбульский А.В., Попов А.М., Артюков А.А., Костецкий Э.Я., Кривошапко О.Н., Мазейка А.Н., Коз- ловская Э.П. Сравнительное изучение лечебного действия лютеолина, розмариновой кислоты и эхинохрома А при экспериментальной кардиопатологии, индуцированной стрессом // Биомедицинская химия, 2011. Т. 57, № 3. С. 314-325. [Tsybulsky A.V., Popov A.M., Artyukov A.A., Kostetsky E.Y., Krivoshapko O.N., Maseyka A.N., Kozlovskava E.P. The comparative study of the medical action of lyuteolin, rosmarinic acid and echinochroma at experimental stress-lnduced cardiopathology. Biomeditsinskaya khimiya = Biomedical Chemistry, 2011, Vol. 57, no. 3, pp. 314-325. (In Russ.)]

13. Цыбульский А.В., Попов А.М., Кривошапко О.Н., Артюков А.А., Козловская Э.П., Богданович Л.Н., Крыжановский С.П., Блинов Ю.Г. Влияние эхинохрома А на биохимические параметры крови у больных с кардиопатологией // Биомедицинская химия, 2014. Т. 60, № 1. С. 115-124. [Tsybulsky A.V., Popov A.M., Artiukhov A.A., Krivoshapko O.N., Kozlovskaya E.P., Bogdanovich L.N., Kryzhanovsky S.P., Blinov I.G. The effects of preparation «Histochrome» in biochemical parameters of blood for patients with cardiopathologies. Biomeditsinskaya khimiya = Biomedical Chemistry, 2014, Vol. 60, no. 1, pp. 115-124. (In Russ.)]

14. Ambati R.R., Phang S.-M., Ravi S., Aswathanarayana R.G. Astaxanthin: sources, extraction, stability, biological activities and its commercial applications. A Review. Marine Drugs, 2014, Vol. 12, no. 1, pp. 128-152.

15. Artyukov A.A., Popov A.M., Tsybulsky A.V., Krivoshapko O.N., Polyakova N.V. Pharmacological activity of echinochrome a alone and in the biologically active additive timarin. Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 2013, Vol. 7, pp. 237-242.

16. Evans J.M., Donnelly L.A., Emslie-Smith A.M., Alessi D.R., Morris A.D. Metformin and reduced risk of cancer of 25-37% in diabetic patients. British Medical Journal, 2005, Vol. 330, pp. 1304-1305.

17. Feng Z., Zhao L., Luo L., You Z., Li D., Xia J., Zuo G., Chen D. Effect of ginsenoside Rh2 on the migratory ability of HepG2 liver carcinoma cells: Recruiting histone deacetylase and inhibiting activator protein 1 transcription factors. Molecular Medicine Reports, 2014, Vol. 10, pp. 1779-1785.

18. Kaiser J. Antioxidants could spur tumors by acting on cancer gene. Science, 2014, Vol. 343, no. 6170, p. 477.

19. Li D., Yeung S.C., Hassan M.M., Konopleva M., Abbruzzese J.L. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology, 2009, Vol. 137, no. 2, pp. 482-488.

20. Libby G., Donnelly L.A., Donnan P.T., Alessi D.R., Morris A.D., Evans J.M. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care, 2009, Vol. 32, pp. 1620-1625.

21. Liu S., Chen M., Li P, Wu Y., Chang C., Qiu Y., Cao L., Liu Z., Jia C. Ginsenoside Rh2 inhibits cancer stemlike cells in skin squamous cell carcinoma cell. Journal of Physiology and Biochemistry, 2015, Vol. 36, pp. 499-508.

22. Loetchutinat C., Kothan S., Dechsupa S., Meesungnoen J., Jay-Gerin J.P., Mankhetkorn S.J. Spectrofluorometric determination of intracellular levels of reactive oxygen species in drug-sensitive and drug-resistant cancer cells using the 2’,7’-dichlorofluorescein diacetate assay. Radiation Physics and Chemistry, 2005, Vol. 72, no. 2-3, pp. 323-331.

23. Popov A.M., Krivoshapko O.N. Protective effects of polar lipids and redox-active compounds from marine organisms at modeling of hyperlipidemia and diabetes. Journal of Biomedical Science and Engineering, 2013, Vol. 6, pp. 543-550.

24. Sayin V.I., Ibrahim M.X., Larsson E., Nilsson J.A., Lindahl P., Bergo M.O. Antioxidants accelerate lung cancer progression in mice. Science Translational Medicine, 2014, Vol. 6, pp. 221-225.

25. Shin H.R., Kim J.Y., Yun T.K., Morgan G., Vainio H. The cancer-preventive potential of Panax ginseng: a review of human and experimantal evidence. Cancer Causes and Control, 2000, Vol. 11, no. 6, pp. 565-576.