Antiproliferative effects of resveratrol and indole-3-carbinol in HPV-associated diseases prevention

   The burden of persistent papillomavirus infection on public healthcare is not limited to cervical cancer (CC). At present, cervical cancer continues to be one of the most common types of cancer worldwide, although HPV also causes anogenital warts. As there is no HPV treatment available, nowadays researchers focus on the search for new therapeutic platforms, new agents for HPV-associated diseases relapse prevention after surgical treatment. Significant anticancer effects of resveratrol have been demonstrated in a variety of cancers, including breast cancer, skin cancer, lung cancer, pancreatic cancer, and stomach cancer. In CC cells, resveratrol stimulates apoptosis of cancer cells, increases expression of HPV E6 and E7, and the expression of p53 tumor suppressor protein. Protective effects on CC cells migration and invasion is achieved by inhibiting NF-κB transcription and AP-1 mediated MMP9 expression. Resveratrol demonstrates a whole range of anti-inflammatory effects, ranging from the suppression of the pro-inflammatory cytokines IL-1α, IL-1β, IL-6, IL-17 expression and inflammatory mediator prostaglandin E2, to the suppression of the formation of ROS and NO. I3K has a proven antitumor efficacy based on the molecular mechanisms of pathological cell proliferation and tumor transformation in hormone- dependent tissues, including cervical epithelial cells. Resveratrol and I3K have a wide range of studied positive therapeutic effects that can significantly reduce the likelihood of development and progression of HPV-associated lesions.

1. Crosbie E. J., Einstein M. H., Franceschi S., Kitchener H. C. Human papillomavirus and cervical cancer. Lancet. 2013; 382 (9895): 889–899. https://doi.org/10.1016/S0140-6736(13)60022-7.

2. Allemani C., Weir H. K., Carreira H., Harewood R., Spika D., Wang X. S. et al. Global surveillance of cancer survival 1995‐2009: analysis of individual data for 25,676,887 patients from 279 population‐based registries in 67 countries (CONCORD‐2). Lancet. 2015; 385: 977–1010. https://doi.org/10.1016/S0140-6736(14)62038-9.

3. Chen W., Zheng R., Baade P. D., Zhang S., Zeng H., Bray F. et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016; 66 (2): 115–132. https://doi.org/10.3322/caac.21338.

4. Mallath M. K. , Taylor D. G., Badwe R. A., Rath G. K., Shanta V., Pramesh C. S. et al. The growing burden of cancer in India: epidemiology and social context. Lancet Oncol. 2014; 15: e205–e212. https://doi.org/10.1016/S1470-2045(14)70115-9.

5. Каприн А. Д. Злокачественные новообразования в России в 2020 году (заболеваемость и смертность) / А. Д. Каприн, В. В. Старинский, А. О. Шахзадова. – М.: МНИОИ им. П. А. Герцена − филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2021. – 252 с. Режим доступа: https://glavonco.ru/cancer_register/%D0%97%D0%B0%D0%B1%D0%BE%D0%BB_2020_%D0%AD%D0%BB%D0%B5%D0%BA%D1%82%D1%80.pdf. – Kaprin A. D., Starinskiy V. V., Shakhzadova A. O. Malignant neoplasms in Russia in 2020 (morbidity and mortality). Moscow: P. Hertsen Moscow Oncology Research Institute – Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation; 2021. 252 p. (In Russ.) Available at: https://glavonco.ru/cancer_register/%D0%97%D0%B0%D0%B1%D0%BE%D0%BB_2020_%D0%AD%D0%BB%D0%B5%D0%BA%D1%82%D1%80.pdf

6. Chesson H. W., Dunne E. F., Hariri S., Markowitz L. E. The estimated life-time probability of acquiring human papillomavirus in the United States. Sex Transm Dis. 2014; 41: 660–664. https://doi.org/10.1097/OLQ.0000000000000193.

7. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Biological agents. Volume 100 B. A review of human carcinogens. IARC Monogr Eval Carcinog Risks Hum. 2012; 100 (Pt. B): 1–441. Available at: https://pubmed.ncbi.nlm.nih.gov/23189750.

8. Bernard H.-U., Bosch F. X., Campo M. S., Cuzick J., Gissmann L., Koutsky L. A. et al. IARC Monographs on the Evaluation of Carcinogenic Risks to Human. IARC, Lyon, France; 1995. Available at: https://monographs.iarc.who.int/wp-content/uploads/2018/06/mono64.pdf.

9. Wilson J. M. G., Maxwell G., Gunnar J.; World Health Organization. Principles and practice of screening for disease. World Health Organization; 1968. Available at: https://apps.who.int/iris/handle/10665/37650.

10. Гусаков К. И. Перспективы профилактики рака, ассоциированного с вирусом папилломы человека / К. И. Гусаков [и др.] // Акушерство и гинекология. – 2019. – (8): 33–39. https://doi.org/10.18565/aig.2019.8.33-39. – Gusakov K. I., Nazarova N. M., Prilepskaya V. N., Starodubtseva N. L., Frankevich V. E. Prospects for the prevention of HPV-associated cancer. Akusherstvo i Ginekologiya (Russian Federation). 2019;(8): 33–39 (In Russ.) https://doi.org/10.18565/aig.2019.8.33-39.

11. Hanahan D., Weinberg R. A. 2011. Hallmarks of cancer: the next generation. Cell. 144: 646–674. https://doi.org/10.1016/j.cell.2011.02.013

12. Schiffman M., Castle P. E., Jeronimo J., Rodriguez A. C., Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007; 370: 890–907. https://doi.org/10.1016/S0140-6736(07)61416-0.

13. Moscicki A. B., Shiboski S., Hills N. K., Powell K. J., Jay N., Hanson E. N. et al. Regression of low‐grade squamous intra‐epithelial lesions in young women. Lancet. 2004; 364: 1678–1683. https://doi.org/10.1016/S0140-6736(04)17354-6.

14. Sendagorta-Cudós E., Burgos-Cibrián J., Rodríguez- Iglesias M. Genital infections due to the human papillomavirus. Enferm Infecc Microbiol Clin (Engl Ed). 2019; 37 (5): 324–334. https://doi.org/10.1016/j.eimc.2019.01.010.

15. Liu M. Z., Hung Y. P., Huang E. C., Howitt B. E., Nucci M. R., Crum C. P. HPV 6-associated HSIL / Squamous Carcinoma in the Anogenital Tract. Int J Gynecol Pathol. 2019; 38 (5): 493–497. https://doi.org/10.1097/PGP.0000000000000556.

16. Ozaydin-Yavuz G., Bilgili S. G., Guducuoglu H., Yavuz I. H., Elibuyuk-Aksac S., Karadag A. S. Determinants of high-risk human papillomavirus infection in anogenital warts. Postepy Dermatol Alergol. 2019; 36 (1): 76–81. https://doi.org/10.5114/ada.2019.82915.

17. Lisboa C., Santo I., Azevedo J., Azevedo L., Pista A., Dias C. et al. High Prevalence of Human Papillomavirus on Anal and Oral Samples from Men and Women with External Anogenital Warts: The HERCOLES Study. Acta Derm Venereol. 2019; 99 (6): 557–563. Available at: https://pubmed.ncbi.nlm.nih.gov/30723872/

18. Yanofsky V. R., Patel R. V., Goldenberg G. Genital warts: a comprehensive review. J Clin Aesthet Dermatol. 2012; 5 (6): 25–36. Available at: https://www.semanticscholar.org/paper/Genital-warts%3A-a-comprehensive-review.-Yanofsky-Patel/4b532c9a5f87e372453f54fccb8db6b67c41a38c.

19. Sichero L., Giuliano A. R., Villa L. L. Human Papillomavirus and Genital Disease in Men: What We Have Learned from the HIM Study. Acta Cytol. 2019; 63 (2): 109–117. https://doi.org/10.1159/000493737.

20. Workowski K. A., Bolan G. A.; Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015; 64 (RR-03): 1–137. Available at: https://pubmed.ncbi.nlm.nih.gov/26042815.

21. Wiley D. J., Douglas J., Beutner K., Cox T., Fife K., Moscicki A. B. et al. External genital warts: diagnosis, treatment, and prevention. Clin Infect Dis. 2002; 35: 210–224. https://doi.org/10.1086/342109.

22. Tyring S., Edwards L., Cherry L. K., Ramsdell W. M., Kotner S., Greenberg M. D. et al. Safety and efficacy of 0.5 % podofilox gel in the treatment of anogenital warts. Arch Dermatol. 1998; 134 (1): 33–38. https://doi.org/10.1001/archderm.134.1.33.

23. Sun X., Fu P., Xie L., Chai S., Xu Q., Zeng L. et al. Resveratrol inhibits the progression of cervical cancer by suppressing the transcription and expression of HPV E6 and E7 genes. Int J Mol Med. 2021; 47 (1): 335–345. https://doi.org/10.3892/ijmm.2020.4789.

24. Kim Y. S., Sull J. W., Sung H. J. Suppressing effect of resveratrol on the migration and invasion of human metastatic lung and cervical cancer cells. Mol Biol Rep. 2012; 39 (9): 8709–8716. https://doi.org/10.1007/s11033-012-1728-3.

25. Zhao Y., Yuan X., Li X., Zhang Y. Resveratrol significantly inhibits the occurrence and development of cervical cancer by regulating phospholipid scramblase 1. J Cell Biochem. 2018. https://doi.org/10.1002/jcb.27335.

26. Sun L., Chen B., Jiang R., Li J., Wang B. Resveratrol inhibits lung cancer growth by suppressing M2-like polarization of tumor associated macrophages. Cell Immunol. 2017; 311: 86–93. https://doi.org/10.1016/j.cellimm.2016.11.002.

27. Male D., Brostoff J., Roth D., Roitt I. Mononuclear Phagocytes in Immune Defense Immunology. 8th ed. Elsevier Saunders; Philadelphia, PA, USA; 2013. https://doi.org/10.1016/B0-323-03399-7/50011-8.

28. Stout R. D., Suttles J. Functional plasticity of macrophages: Reversible adaptation to changing microenvironments. J Leukoc Biol. 2004; 76: 509–513. https://doi.org/10.1189/jlb.0504272.

29. Ries C. H., Cannarile M. A., Hoves S., Benz J., Wartha K., Runza V. et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell. 2014; 25: 846–859. https://doi.org/10.1016/j.ccr.2014.05.016.

30. Gao X., Xu Y. X., Janakiraman N., Chapman R. A., Gautam S. C. Immunomodulatory activity of resveratrol: Suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production. Biochem Pharmacol. 2001; 62: 1299–1308. https://doi.org/10.1016/S0006-2952(01)00775-4.

31. Fuggetta M. P., Bordignon V., Cottarelli A., Macchi B., Frezza C., Cordiali-Fei P. et al. Downregulation of proinflammatory cytokines in HTLV-1-infected T cells by Resveratrol. J Exp Clin Cancer Res. 2016; 35: 118. https://doi.org/10.1186/s13046-016-0398-8.

32. Xian Y., Gao Y., Lv W., Ma X., Hu J., Chi J. et al. Resveratrol prevents diabetic nephropathy by reducing chronic inflammation and improving the blood glucose memory effect in non-obese diabetic mice. Naunyn Schmiedebergs Arch Pharmacol. 2020; 393 (10): 2009–2017. https://doi.org/10.1007/s00210-019-01777-1.

33. Zhong L. M., Zong Y., Sun L., Guo J. Z., Zhang W., He Y. et al. Resveratrol inhibits inflammatory responses via the mammalian target of rapamycin signaling pathway in cultured LPS-stimulated microglial cells. PLoS ONE. 2012; 7: e32195. https://doi.org/10.1371/journal.pone.0032195.

34. Lopes Pinheiro D. M., Sales de Oliveira A. H., Coutinho L. G., Fontes F. L., de Medeiros Oliveira R. K., Oliveira T. T. et al. Resveratrol decreases the expression of genes involved in inflammation through transcriptional regulation. Free Radic Biol Med. 2019; 130: 8–22. https://doi.org/10.1016/j.freeradbiomed.2018.10.432.

35. Saqib U., Kelley T. T., Panguluri S. K., Liu D., Savai R., Baig M. S. et al. Polypharmacology or Promiscuity? Structural Interactions of Resveratrol with Its Bandwagon of Targets. Front Pharmacol. 2018; 9: 1201. https://doi.org/10.3389/fphar.2018.01201.

36. Lee C. W., Wong L. L., Tse E. Y., Liu H. F., Leong V. Y., Lee J. M. et al. AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells. Cancer Res. 2012; 72 (17): 4394–4404. https://doi.org/10.1158/0008-5472.CAN-12-0429.

37. Gao B., Kong Q., Kemp K., Zhao Y. S., Fang D. Analysis of sirtuin 1 expression reveals a molecular explanation of IL-2-mediated reversal of T-cell tolerance. Proc Natl Acad Sci USA. 2012; 109: 899–904. https://doi.org/10.1073/pnas.1118462109.

38. Borra M. T., Smith B. C., Denu J. M. Mechanism of human SIRT1 activation by Resveratrol. J Biol Chem. 2005; 280 (17): 17187–17195. https://doi.org/10.1074/jbc.M501250200.

39. Xuzhu G., Komai-Koma M., Leung B. P., Howe H. S., McSharry C., McInnes I. B., Xu D. Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function. Ann Rheum Dis. 2012; 71: 129–135. https://doi.org/10.1136/ard.2011.149831.

40. Yamamoto Y., Gaynor R. B. Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer. J Clin Investig. 2001; 107: 135–142. https://doi.org/10.1172/JCI11914.

41. Liu L. L., He J. H., Xie H. B., Yang Y. S., Li J. C., Zou Y. Resveratrol induces antioxidant and heat shock protein mRNA expression in response to heat stress in black-boned chickens. Poult Sci. 2014; 93: 54–62. https://doi.org/10.3382/ps.2013-03423.

42. Reuter S., Gupta S. C., Chaturvedi M. M., Aggarwal B. B. Oxidative stress, inflammation, and cancer: How are they linked? Free Radic Biol Med. 2010; 49: 1603–1616. https://doi.org/10.1016/j.freeradbiomed.2010.09.006.

43. Tsai S. H., Lin-Shiau S. Y., Lin J. K. Suppression of nitric oxide synthase and the down-regulation of the activation of NF-kappa B in macrophages by resveratrol. Br J Pharmacol. 1999; 126: 673–680. https://doi.org/10.1038/sj.bjp.0702357.

44. Das A. Heat stress- induced hepatotoxicity and its prevention by resveratrol in rats. Toxicol Mech Methods. 2011; 21 (5): 393–399. https://doi.org/10.3109/15376516.2010.550016.

45. Hou Y., Zhang Y., Mi Y., Wang J., Zhang H., Xu J. et al. A Novel Quinolyl-Substituted Analogue of Resveratrol Inhibits LPS-Induced Inflammatory Responses in Microglial Cells by Blocking the NF-κB/MAPK Signaling Pathways. Mol Nutr Food Res. 2019; 63: e1801380. https://doi.org/10.1002/mnfr.201801380.

46. Jiang H., Duan J., Xu K., Zhang W. Resveratrol protects against asthma-induced airway inflammation and remodeling by inhibiting the HMGB1 / TLR4/NF-kappa B pathway. Exp Ther Med. 2019; 18 (1): 459–466. https://doi.org/10.3892/etm.2019.7594.

47. Rietschel E. T., Kirikae T., Schade F. U., Mamat U., Schmidt G., Loppnow H. et al. Bacterial endotoxin: Molecular relationships of structure to activity and function. FASEB J. 1994; 8: 217–225. https://doi.org/10.1096/fasebj.8.2.8119492.

48. Palomera-Avalos V., Grinan-Ferre C., Izquierdo V., Camins A., Sanfeliu C., Canudas A. M., Pallas M. Resveratrol modulates response against acute inflammatory stimuli in aged mouse brain. Exp Gerontol. 2018; 102: 3–11. https://doi.org/10.1016/j.exger.2017.11.014.

49. Singh A. P., Singh R., Verma S. S., Rai V., Kaschula C. H., Maiti P., Gupta S. C. Health benefits of resveratrol: Evidence from clinical studies. Med Res Rev. 2019; 39 (5): 1851–1891. https://doi.org/10.1002/med.21565.

50. Piver B., Berthou F., Dreano Y., Lucas D. Inhibition of CYP3A, CYP1A and CYP2E1 activities by resveratrol and other non volatile red wine components. Toxicol Lett. 2001; 125 (1–3): 83–91. https://doi.org/10.1016/s0378-4274(01)00418-0.

51. Винокурова Е. А. Новые возможности персонифицированной менопаузальной фитотерапии ресвератролом / Е. А. Винокурова, Д. Х. Исмаилова, Т. Н. Хвощина // Доктор.Ру. – 2021. – 20 (6): 92–96. https://doi.org/10.31550/1727-2378-2021-20-6-92-96. – Vinokurova E. A., Ismailova D. Kh., Khvoschina T. N. New Possibilities of Personalised Menopausal Phytotherapy with Resveratrol. Doctor.Ru. 2021; 20 (6): 92–96. (In Russ.) https://doi.org/10.31550/1727-2378-2021-20-6-92-96.

52. Sharma S., Chopra K., Kulkarni S. K., Agrewala J. N. Resveratrol and curcumin suppress immune response through CD28 / CTLA-4 and CD80 co-stimulatory pathway. Clin Exp Immunol. 2007; 147: 155–163. https://doi.org/10.1111/j.1365-2249.2006.03257.x.

53. Švajger U., Jeras M. Anti-inflammatory effects of Resveratrol and its potential use in therapy of immune- mediated diseases. Int Rev Immunol. 2012; 31: 202–222. https://doi.org/10.3109/08830185.2012.665108.

54. Mahal H. S., Mukherjee T. Scavenging of reactive oxygen radicals by Resveratrol: Antioxidant effect. Res Chem Intermed. 2006; 32: 59–71. https://doi.org/10.1163/156856706775012941.

55. Szewczuk L. M., Forti L., Stivala L. A., Penning T. M. Resveratrol is a peroxidase mediated inactivator of COX-1 but not COX-2: A mechanistic approach to the design of COX-1 selective agents. J Biol Chem. 2004; 279: 22727–22737. https://doi.org/10.1074/jbc.M314302200.

56. Evans H. M., Howe P. R., Wong R. H. Effects of resveratrol on cognitive performance, mood and cerebrovascular function in post-menopausal women: a 14-week randomised placebo- controlled intervention trial. Nutrients. 2017; 9 (1): 27. https://doi.org/10.3390/nu9010027.

57. Davinelli S., Scapagnini G., Marzatico F., Nobile V., Ferrara N., Corbi G. Influence of equol and resveratrol supplementation on health-related quality of life in menopausal women: A randomized, placebo-controlled study. Maturitas. 2017; 96: 77–83. https://doi.org/10.1016/j.maturitas.2016.11.016.

58. Киселев В. И. Консервативная терапия CIN I-II вагинальными суппозиториями цервикон-дим (промежуточные результаты клинического исследования) / В. И. Киселев [и др.] // Медицинский cовет. – 2014. – (17): 140–143. URL: https://www.med-sovet.pro/jour/article/view/790?locale=ru_RU. – Kiselyov V. I., Drukh V. M., Kuznetsov I. N., Muyahnek E. L., Apolikhina I. A., Gorbunova E. A., Pchelintseva O. I. Conservative therapy with CIN I-II vaginal suppositories Cervicon-Dim (intermediate results of a clinical study). Meditsinskiy Sovet. 2014; (17): 140–143. (In Russ.) URL: https://www.med-sovet.pro/jour/article/view/790?locale=ru_RU.

59. Куценко И. И. Опыт клинического применения дииндолилметана в лечении ассоциированного с вирусом папилломы человека цервикального поражения низкой степени / И. И. Куценко [и др.] // Медицинский cовет. – 2020. – (3): 25–31. https://doi.org/10.21518/2079-701X-2020-3-25-31. – Kutsenko I. I., Borovikov I. O., Gorring H. I., Magay A. S., Gorbulina A. A. Experience of clinical use of diindolylmethane in the treatment of HPV-associated low-grade cervical lesions. Meditsinskiy Sovet. 2020; (3): 25–31. (In Russ.) https://doi.org/10.21518/2079-701X-2020-3-25-31.

60. Cantley L. C., Neel B. G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase / AKT pathway. Proc Natl Acad Sci USA. 1999; 96 (8): 4240–4245. https://doi.org/10.1073/pnas.96.8.4240.

61. Chen D. Z., Qi M., Auborn K. J., Carter T. H. Indole-3-carbinol and diindolyl-methane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium. J Nutr. 2001; 131 (12): 3294–302. https://doi.org/10.1093/jn/131.12.3294.

62. Cheung T. H., Lo K. W., Yim S. F., Chan L. K., Heung M. S., Chan C. S. et al. Epigenetic and genetic alternation of PTEN in cervical neoplasm. Gynecol Oncol. 2004; 93 (3): 621–627. https://doi.org/10.1016/j.ygyno.2004.03.013.

63. Banerjee S., Kong D., Wang Z., Bao B., Hillman G. G., Sarkar F. H. Attenuation of multi-targeted proliferation-linked signaling by 3,3’-diindolylmethane (DIM): from bench to clinic. Mutat Res. 2011; 728 (1–2): 47–66. https://doi.org/10.1016/j.mrrev.2011.06.001.

64. Sepkovic D. W., Stein J., Carlisle A. D., Ksieski H. B., Auborn K., Bradlow H. L. Diindolylmethane inhibits cervical dysplasia, alters estrogen metabolism, and enhances immune response in the K14-HPV16 transgenic mouse model. Cancer Epidemiol Biomarkers Prev. 2009; 18 (11): 2957–2964. https://doi.org/10.1158/1055-9965.EPI-09-0698.

65. Del Priore G., Gudipudi D. K., Montemarano N., Restivo A. M., Malanowska-Stega J., Arslan A. A. Oral diindolylmethane (DIM): pilot evaluation of a nonsurgical treatment for cervical dysplasia. Gynecol Oncol. 2010; 116 (3): 464–467. https://doi.org/10.1016/j.ygyno.2009.10.060.

66. Сухих Г. Т. Исследование эффективности и безопасности препарата на основе дииндолилметана у пациенток с цервикальной интраэпителиальной неоплазией (CIN 1–2) / Г. Т. Сухих [и др.] // Акушерство и гинекология. – 2018. – (9): 91–98. https://doi.org/10.18565/aig.2018.9.91-98. – Sukhikh G. T., Ashrafyan L. A., Kiselev V. I., Apolikhina I. A., Maltseva L. I., Suturina L. V. et al. Investigation of the efficacy and safety of a diindolylmethane- based drug in patients with cervical intraepithelial neoplasia grades 1-2 (CIN 1–2). Akusherstvo i Ginekologiya (Russian Federation). 2018; (9): 91–98. (In Russ.) https://doi.org/10.18565/aig.2018.9.91-98.

67. Banerjee S., Kong D., Wang Z., Bao B., Hillman G. G., Sarkar F. H. Attenuation of multi-targeted proliferation-linked signaling by 3,3’-diindolylmethane (DIM): from bench to clinic. Mutat Res. 2011; 728(1–2): 47–66. https://doi.org/10.1016/j.mrrev.2011.06.001.

68. Weng J. R., Tsai C. H., Kulp S. K., Chen C. S. Indole-3-carbinol as a chemopreventive and anti-cancer agent. Cancer Lett. 2008; 262 (2): 153–163. https://doi.org/10.1016/j.canlet.2008.01.033.

69. Боровиков И. О. Опыт применения иммуномодулирующего препарата в терапии папилломавирусной инфекции гениталий у женщин / И. О. Боровиков, И. И. Куценко, Х. И. Горринг // Акушерство и гинекология. – 2018. – (3): 122–128. https://doi.org/10.18565/aig.2018.3.122-128. – Borovikov I. O., Kutsenko I. I., Gorring C. I. Experience of using the immuno-modulator in the therapy of papillomavirus infection of genitalia in women. Akusherstvo i Ginekologiya (Russian Federation). 2018; (3): 122–128. (In Russ.) https://doi.org/10.18565/aig.2018.3.122-128.

70. Wu T. Y., Khor T. O., Su Z. Y., Saw C. L., Shu L., Cheung K. L. et al. Epigenetic modifications of Nrf2 by 3,3’-diindolylmethane in vitro in TRAMP C1 cell line and in vivo TRAMP prostate tumors. The AAPS J. 2013; 15 (3): 864–874. https://doi.org/10.1208/s12248-013-9493-3.

71. Semov A., Iourtchenko L., Liu L., Xu Y., Su X., Muyjnek E. et al. Diindolyl-methane (DIM) selectively inhibits cancer stem cells. Biochem Biophys Res Commun. 2012; 424 (1): 45–51. https://doi.org/10.1016/j.bbrc.2012.06.062.

72. Кузнецов И. Н. Доклиническое исследование влияния новой фармацевтической композиции на основе 3,3’-дииндолилметана на репродуктивную функцию и иммунную систему / И. Н. Кузнецов [и др.] // Вестник Российского научного центра рентгенорадиологии. – 2013. – 13 (3): 1–8. Режим доступа: https://www.elibrary.ru/item.asp?id=20778244. – Kuznetsov I. N., Ashrafyan L. A., Kiselev V. I., Drukh V. M., Muyzhnek E. L., Pchelintseva O. I. et al. Preclinical study of effects of a novel 3,3’-diindolyl-methane based pharmaceutical composition on reproductive function and immune system. Russian Scientific Center of Roentgenoradiology. 2013; 13 (3): 1–8. (In Russ.) Available at: https://www.elibrary.ru/item.asp?id=20778244.

73. Чуруксаева О. Н. Физиохирургические методы лечения вирус-ассоциированной патологии шейки матки / О. Н. Чуруксаева, Л. А. Коломиец // Сибирский онкологический журнал. – 2011. – (3): 11–15. Режим доступа: https://onco.tnimc.ru/upload/zhurnal/soj_2011_3_11-15.pdf. – Churuksayeva O. N., Kolomiets L. A. Physiosurgical treatment methods for virus-associated cervical lesions. Siberian Journal of Oncology. 2011; (3): 11–15. (In Russ.) Available at: https://onco.tnimc.ru/upload/zhurnal/soj_2011_3_11-15.pdf.

74. Киселев В. И. Способ лечения плоскоклеточных интраэпителиальных поражений шейки матки / В. И. Киселев, В. М. Друх, И. Н. Кузнецов. – Свидетельство Роспатента о государственной регистрации базы данных № RU2552332C1. – 2014. Режим доступа: https://patents.google.com/patent/RU2552332C1/ru. – Kiselev V. I., Drukh V. M., Kuznetsov I. N. Method of treating of planocellular intraepithelial lesions of cervix of uterus. Rospatent Certificate of State Registration of a Database No. RU2552332C1. 2014. (In Russ.) Available at: https://patents.google.com/patent/RU2552332C1/ru.

75. Mohanty K. C., Scott C. S. Immunotherapy of genital warts with inosine pranobex (Imunovir): preliminary study. Genitourin Med. 1986; 62 (5): 352–355. URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1011990/

76. Berth-Jones J., Hutchinson P. E. Modern treatment of warts: cure rates at 3 and 6 months. Br J Dermatol. 1992; 127 (3): 262–265. https://doi.org/10.1111/j.1365-2133.1992.tb00125.x.