Current principles of effective therapy for ovarian cancer

In spite of all of modern medicine»s advances, ovarian cancer (OC) mortality remains to be incommensurably high and to hold the lead among gynecological cancers. The initial cause of this deplorable statistics is the absence of a clear concept of the pathogenesis of OC and hence the justified prevention and methodology of early diagnosis of the disease; in this connection, therapy that proves to be ineffective is frequently used by medical oncologists in their daily practice. As a consequence, there is a high proportion of its further progression: the rates of early and late recurrences were about 30 and 60–65 %, respectively; most of which are drug resistant to further chemotherapy cycles. By taking into account these strikingly modest statistics, it becomes apparent that oncologists desire to make changes in the existing treatment regimen to achieve meaningful results. To use target drugs is one of these promising areas owing to new views on the concept of the pathogenesis of OC.
Nevertheless, considering a wide variety of the signaling cascades and molecules, which are involved in the process of carcinogenesis, even target compounds, if they have only one point of application, cannot always produce their desirable therapeutic effect and their co-administration is responsible for high toxicity. In this light, the most effective drugs are indole-3-carbinol and epigallocathechin-3-gallate, which virtually cause no adverse reactions and can block various molecular targets at different levels of the mechanism of malignant transformation. Based on L. A. Ashrafyan, s concept of two pathogenetic variants of sporadic OC (2009) and on the recent findings in molecular biology and epigenetics, the incorporation of the above medications into the standard treatment regimen for OC should increase survival rates and change the nature of recurrence by that of more locally advanced forms. On this basis, a clinical trial was carried out to study the efficiency of using antitumor drugs based on indole-3-carbinol and epigallocathechin-3-gallate as part of combination therapy for OC. The results of the clinical trial performed are suggestive of considerably higher survival rates in the groups receiving the above drugs than in the control groups. In addition, the multitarget effect of indole-3-carbinol and epigallocathechin-3-gallate can effectively remodel the function of a cancer stem cell, the main source of recurrences and metastases, and may be considered as an important adjunct to the existing strategy of antitumor therapy.

1. Козаченко В. П. Клиническая онкология. Руководство для врачей. М.: Медицина, 2005. 376 с. [Kozachenko V.P. Clinical oncology. Manual for physicians. Moscow: Meditsina, 2005. 376 p. (In Russ.)].

2. Каприн А.Д., Старинский В. В., Петрова Г. В. Злокачественные новообразования в России в 2013 году (заболеваемость и смертность). М., 2015. С. 12–3; 16; 19; 136; 143. [Kaprin A.D., Starinskiy V.V., Petrova G.V. Malignant neoplasms in Russia in 2013 (morbidity and mortality rate). Moscow, 2015. Pp. 12–3; 16; 19; 136; 143. (In Russ.)].

3. Давыдов М. И., Аксель Е. М. Статистика злокачественных новообразований в России и странах СНГ в 2012 г. М.: РОНЦ им. Н. Н. Блохина РАМН, 2014. С. 15; 158. [Davydov M.I., Axel E.M. Statistics of malignant neoplasms in Russia and CIS countries in 2012. Moscow: RONC im. N.N. Blokhina RAMS, 2014. Pp. 15; 158. (In Russ.)].

4. Ferlay J., Soerjomataram I., Ervik M. et al. Cancer incidence and mortality worldwide: IARC Cancer Base No. 11 GLOBOCAN 2012 v1.0. Available from: http://globocan.iarc.fr.

5. Bray F., Ren J. S., Masuyer E. Ferlay J. Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer 2013;132(5):1133–45.

6. http://www.cancer.org/cancer/ovariancancer/detailedguide/ovarian-cancersurvival-rates.

7. http://www.cancer.org/cancer/ovariancancer/detailedguide/ovarian-cancerrisk-factors.

8. Бохман Я. В. Лекции по онкогинекологии. М.: Медицинское информационное агентство, 2007. С. 26. [Bokhman Ya.V. Lectures on oncogynecology. Moscow: Meditsinskoye informatsionnoye agentstvo, 2007. p. 26. (In Russ.)].

9. Герфанова Е.В., Ашрафян Л. А., Антонова И. Б. и др. Скрининг рака яичников: реальность и перспективы. Обзор литературы. Опухоли женской репродуктивной системы 2015;(1):69–75. [Gerfanova E.V., Ashrafyan L.A., Antonova I.B. et al. Ovarian cancer screening: reality and prospects. Review of references. Opukholi zhenskoy reproduktivnoy sistemy = Tumors of Female Reproductive System. 2015;(1):69–75. (In Russ.)].

10. Husseinzadeh N. Status of tumor markers in epithelial ovarian cancer has there been any progress? A review. Gynecol Oncol 2011;120(1):152–7.

11. Kandala P. K., Srivastava S. K. DIMming Ovarian Cancer Growth. Curr Drug Targets 2012;13(14):1869–75.

12. Taylor-Harding B., Agadjanian H., Nassanian H. et al. Indole-3-carbinol synergistically sensitizes ovarian cancer cells to bortezomib treatment. Br J Cancer 2012;106(2):333–43.

13. Гарин А. М., Базин И. С. Таргетная терапия солидных опухолей. Лекарственная противоопухолевая терапия: Альманах. М., 2010. С. 16–49. [Garin A.M., Bazin I.S. Target therapy of solid tumors. Medicinal anticancer therapy: almanac. Moscow, 2010. Pp. 16–49. (In Russ.)].

14. Weinberg R. A. The biology of cancer. N.-Y.: Garland Science, 2007. 794 p.

15. Hanahan D., Weinberg R. A. The hallmarks of cancer. Cell 2000;100(1):57–70.

16. Kaye S., Brown R., Gabra H. et al. Emerging therapeutic targets in ovarian cancer. N.-Y.: Springer Science&Business Media, 2011.

17. Ашрафян Л. А., Киселев В. И., Муйжнек Е. Л. Патогенетическая профилактика рака репродуктивных органов. М.: Димитрейд График Групп, 2009. С. 27–45. [Ashrafyan L.A., Kiselyov V.I., Muizhnek E.L. Pathogenic prevention of cancer of reproductive organs. Moscow: Dimitreyd Graphik Grupp, 2009. Pp. 27–45. (In Russ.)].

18. Ашрафян Л. А., Киселев В. И., Муйжнек Е. Л. и др. Рак яичников: концепция патогенеза и принципы терапии. Онкогинекология. Журнал им. А. П. Герцена 2015;3:23–32. [Ashrafyan L.A., Kiselyov V.I., Muizhnek E.L. et al. Ovarian cancer: pathogenesis concept and therapy principles. Onkoginekologiya. Zhurnal A.P. Gertsena = Oncogynecology. A.P. Herzen Journal 2015;4:453. (In Russ.)].

19. Rao S. D., Pagidas K. Epigallocatechin-3-gallate, a natural polyphenol, inhibits cell proliferation and induces poptosis in human ovarian cancer cells. Anticancer Res 2010;30(7):2519–23.

20. Spinella F., Rosan L., Di Castro V. et al. Green tea polyphenol epigallocatechin-3- gallate inhibits the endothelin axis and downstream signaling pathways in ovarian carcinoma. Mol Cancer Ther 2006;5(6): 1483–92.

21. Raj M. H., Abd Elmageed Z. Y., Zhou J. et al. Synergistic action of dietary phytoantioxidants on survival and proliferation of ovarian cancer cells. Gynecol Oncol 2008;110(3):432–8.

22. Lim T. K. Edible medicinal and nonmedicinal plants. Vol. 7. Flowers. Springer, 2014. Pp. 571–94.

23. Киселев В. И. Описание изобретения к патенту RU2315594 «Антиэстрогенное и антипролиферативное средство для лечения и профилактики заболеваний женской репродуктивной системы». Роспатент, 2006. [Kiselyov V.I. Description of invention to patent RU2315594 “Antiestrogen and anti-proliferative drug for treatment and prevention of diseases of the female reproductive system”. Rospatent, 2006. (In Russ.)].

24. Ашрафян Л. А., Киселев В. И., Муйжнек Е. Л. Систематические ошибки в лечебных подходах к раку яичников. Практическая онкология 2014; 15(4):186–95. [Ashrafyan L.A., Kiselyov V.I., Muizhnek E.L. Systematic errors in treatment approaches to ovarian cancer. Prakticheskaya onkologiya = Practical Oncology 2014;15(4):186–95. (In Russ.)].

25. Rezaei N. Cancer immunology: cancer immunotherapy for organ-specific tumors. Springer, 2015. Pp. 413–37.

26. Ашрафян Л. А. Спорадический рак яичников: вероятная модель патогенеза. Журнал акушерства и женских болезней 2012;61(4):3–10. [Ashrafyan L.A. Sporadic ovarian cancer: probable pathogenesis model. Zhurnal akusherstva I zhenskih bolezney = Journal of Obstetrics and Female Diseases 2012;61(4):3–10. (In Russ.)].

27. Ahmed N., Abubaker K., Findlay J. et al. Cancerous ovarian stem cells: obscure targets for therapy but relevant to chemoresistance. J Cell Biochem 2013;114(1):21–34.

28. Foster R., Buckanovich R. J., Rueda B. R. Ovarian cancer stem cells: Working towards the root of stemness. Cancer Lett 2013;338(1):147–57.

29. Maruthanila V. L., Poornima J., Mirunalini S. Attenuation of carcinogenesis and the mechanism underlying by the influence of indole-3-carbinol and its metabolite 3,3 , -diindolylmethane: a therapeutic marvel. Adv Pharmacol Sci 2014;2014:832161.

30. Hong C., Kim Н. А., Firestone G. L., Bjeldanes L. F. 3,3 ,-Diindolyl-methane (DIM) induces a G (1) cell cycle arrest in human breast cancer cells that is accompanied by Sp1-mediated activation of p21 (WAF1/CIP1) expression. Carcinogenesis 2002;23(8):1297–305.

31. Smigel K. Breast cancer prevention trial shows major benefit, some risk. J Natl Cancer Inst 1998;90(9):647–8.

32. Chinni S. R., Sarkar F. H. Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells. Clin Cancer Res 2002;8(4):1228–36.

33. Brignall M. S. Prevention and treatment of cancer with indole-3-carbinol. Altem Med Rev 2001;6(6):580–9.

34. Aggarwal B. B., Ichikawa H. Molecular targets and anticancer potential of indole-3- carbinol and its derivatives. Cell Cycle 2005;4(9):1201–15.

35. Powles T. J. Efficacy of tamoxifen as treatment of breast cancer. Semin Oncol 1997;24(1 Suppl 1):S1-48–54.

36. Киселев В. И., Муйжнек Е. Л. Описание изобретения к патенту RU2328282 «Фармацевтическая композиция для профилактики метастазов и повышения чувствительности опухолей к химиотерапевтическим препаратам». Роспатент, 2007. [Kiselyov V.I., Muizhnek E.L. Description of invention to patent RU2328282 “Pharmaceutical composition for prevention of metastases and increasing of sensitivity of tumors to chemotherapy drugs”. Rospatent, 2007. (In Russ.)].

37. Yang S. C., Bristow R. E., Armstrong D. K. Early diagnosis and treatment of cancer. Ovarian Cancer 2010:234.

38. Kim M. K., Kim K., Han J. H. et al. Modulation of inflammatory signaling pathways by phytochemicals in ovarian cancer. Genes Nutr 2011;6(2):109–15.

39. Steffensen K. D., Alvero A. B., Yang Y. et al. Prevalence of epithelial ovarian cancer stem cells correlates with recurrence in early-stage ovarian cancer. J Oncol 2011;2011:620523. 40. Tang C., Ang B. T., Pervaiz S. Cancer stem cell: target for anti-cancer therapy. FASEB J 2007;21(14):3777–85.