A new paradigm in cervical neoplasia progression: from fundamental knowledge to practical gynecology

Kiselev V.I., Muyzhnek E.L., Ashrafyan L.A., Sukhikh G.T.

1 Institute of Gynecologic Oncology and Mammology, Acad. V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, Moscow 2 AO “MiraxBioFarma”, Moscow 3 Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, Moscow
The mainstay of treatment for precancerous cervical neoplastic diseases caused by human papillomavirus (HPV) continues to be surgical techniques (laser destruction, loop electrosurgical excision, cryodestruction, and cold-knife conization) that are accompanied by high complication and recurrence rates and negatively affect female reproductive function. The etiopathogenetic therapy of cervical intraepithelial neoplasia (CIN), which affects the key mechanisms for the hyperproliferation and tumor transformation of HPV-infected cervical epithelial cells, is becoming increasingly important now. Cervicon-DIM is the world’s first and only 3,3’-diindolylmethane-based drug used to treat CIN, regardless of whether HPV infection is detected by PCP. Acting locally, Cervicon-DIM versus placebo stimulates apoptosis of virus-infected and -transformed cells and substantially increases the likelihood of regression of cervical dysplasia.

Keywords

cervical intraepithelial neoplasia
CIN 1
CIN 2
CIN 3
3-3’-diindolylmethane
vaginal suppositories
medical treatment
secondary prevention of cervical cancer

References

  1. GLOBOCAN, 2018. Estimated cancer incidence, mortality and prevalence worldwide in 2018. Agency for Research on Cancer (IARC); WHO. Available at: http://gco.iarc.fr/
  2. Каприн А.Д., Старинский В.В., Петрова Г.В., ред. Злокачественные новообразования в России в 2017 году (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена - филиал ФГБУ «НМИЦ радиологии» Минздрава России; 2018. [Kaprin A.D., Starinsky V.V., Petrova G.V., ed. Malignant neoplasms in Russia in 2017 (morbidity and mortality). M .: Moscow them. P.A. Herzen - a branch of the Federal Research Center for Radiology Research Center of the Ministry of Health of Russia; 2018. (in Russian)]
  3. La Vecchia C., Boccia S. Oral contraceptives, human papillomavirus and cervical cancer. Eur. J. Cancer Prev. 2014: 23(2): 110-2.
  4. Протасова А.Э., Дзюбий Т.И., Раскин Г.А., Тапильская Н.И., Зазерская И.Е., Хаджиева Э.В. Дисплазия шейки матки – этиопатогенез, диагностика, оптимальная тактика лечения. Учебное пособие. СПб.: МЗ РФ ФГБУ «ФМИЦ им. В.А. Алмазова» кафедра акушерства и гинекологии, СЗГМУ им. И.И. Мечникова каф.едра онкологии; 2014. 22с. [Protasova A.E., Dzyubiy T.I., Raskin G.A., Tapilskaya N.I., Zazerskaya I.E., Khadzhieva E.V. Cervical dysplasia - etiopathogenesis, diagnosis, optimal treatment tactics. Tutorial. SPb .: the Ministry of Health of the Russian Federation V.A. Almazov Department of Obstetrics and Gynecology, North-Western State Medical University named after I.I. Mechnikov Department of Oncology; 2014. 22p. (in Russian)]
  5. Ochs K., Meili G., Diebold J., Arndt V., Günthert A. Incidence trends of cervical cancer and its precancerous lesions in women of Central Switzerland from 2000 until 2014. Front. Med. (Lausanne). 2018; 5: 58.
  6. Steenbergen R.D., Snijders P.J., Heideman D.A., Meijer C.J. Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions. Nat. Rev. Cancer. 2014; 14(6): 395-405.
  7. Mittal S., Banks L. Molecular mechanisms underlying human papillomavirus E6 and E7 oncoprotein-induced cell transformation. Mutat. Res. Rev. Mutat. Res. 2017; 772: 23-35.
  8. Saavedra K.P., Brebi P.M., Roa J.C. Epigenetic alterations in preneoplastic and neoplastic lesions of the cervix. Clin. Epigenetics. 2012; 4(1): 13.
  9. Au Yeung C.L., Tsang W.P., Tsang T.Y., Co N.N., Yau P.L., Kwok T.T. HPV-16 E6 upregulation of DNMT1 through repression of tumor suppressor p53. Oncol. Rep. 2010; 24(6): 1599-604.
  10. Sano D., Oridate N. The molecular mechanism of human papillomavirus‑induced carcinogenesis in head and neck squamous cell carcinoma. Int. J. Clin. Oncol. 2016; 21(5): 819-26.
  11. Huang L.W., Chao S.L., Lee B.H. Integration of human papillomavirus type-16 and type-18 is a very early event in cervical carcinogenesis. J. Clin. Pathol. 2008; 61(5): 627-31.
  12. Kerdraon O., Cornélius A., Farine M.O., Boulanger L., Wacrenier A. Adenoid basal hyperplasia of the uterine cervix: a lesion of reserve cell type, distinct from adenoid basal carcinoma. Hum. Pathol. 2012; 43(12): 2255-65.
  13. Martens J.E., Smedts F.M., Ploeger D., Helmerhorst T.J., Ramaekers F.C., Arends J.W., Hopman A.H. Distribution pattern and marker profile show two subpopulations of reserve cells in the endocervical canal. Int. J. Gynecol. Pathol. 2009; 28(4): 381-8.
  14. Herfs M., Parra-Herran C., Howitt B.E., Laury A.R., Nucci M.R., Feldman S. et al. Cervical squamocolumnar junction-specific markers define distinct, clinically relevant subsets of low-grade squamous intraepithelial lesions. Am. J. Surg. Pathol. 2013; 37(9): 1311-8.
  15. Feng D., Peng C., Li C., Zhou Y., Li M., Ling B. et al. Identification and characterization of cancer stem-like cells from primary carcinoma of the cervix uteri. Oncol. Rep. 2009; 22(5): 1129-34.
  16. López J., Ruíz G., Organista-Nava J., Gariglio P., García-Carrancá A. Human papillomavirus infections and cancer stem cells of tumors from the uterine cervix. Open Virol. J. 2012; 6: 232-40.
  17. 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.
  18. Киселев В.И., Ашрафян Л.А., Друх В.М., Муйжнек Е.Л., Кузнецов И.Н., Пчелинцева О.И., Андрианова Е.А., Барановский П.М. Клиническое исследование по изучению эффективности суппозиториев «Цервикон-ДИМ» при лечении цервикальной интраэпителиальной неоплазии легкой и средней степени. Вестник Российского научного центра рентгенорадиологии Минздрава России. 2014; 14-3: 6. [Kiselev V.I., Ashrafyan L.A., Drukh V.M., Muyzhnek E.L., Kuznetsov I.N., Pchelintseva O.I., Andrianova E.A., Baranovsky P.M. Clinical study on the effectiveness of cervicon-DIM suppositories in the treatment of mild to moderate cervical intraepithelial neoplasia. Bulletin of the Russian Scientific Center for X-ray Radiology of the Ministry of Health of Russia. 2014; 14-3: 6. (in Russian)]
  19. 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.
  20. 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): 2957-64.
  21. 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): 464-7.
  22. Киселев В.И. Молекулярные механизмы патогенеза гиперпластических и диспластических заболеваний репродуктивной системы и пути их фармакологической коррекции. В кн.: Прилепская В.Н., ред. Патология шейки матки и генитальные инфекции. М.: МЕДпресс-информ; 2008: 53-60. [Kiselev V.I. Molecular mechanisms of the pathogenesis of hyperplastic and dysplastic diseases of the reproductive system and ways of their pharmacological correction. In: Prilepskaya VN, ed. Pathology of the cervix and genital infections. M .: MEDpress-inform; 2008: 53-60. (in Russian)]
  23. Zhu J., Li Y., Guan C., Chen Z. Anti-proliferative and pro-apoptotic effects of 3,3’-diindolylmethane in human cervical cancer cells. Oncol. Rep. 2012; 28(3): 1063-8.
  24. 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. AAPS J. 2013; 15(3): 864-74.
  25. Wong C.P., Hsu A., Buchanan A., Palomera-Sanchez Z., Beaver L.M., Houseman E.A. et al. Effects of sulforaphane and 3,3’-diindolylmethane on genome-wide promoter methylation in normal prostate epithelial cells and prostate cancer cells. PLoS One. 2014; 9(1): e86787.
  26. Beaver L.M., Yu T.W., Sokolowski E.I., Williams D.E., Dashwood R.H., Ho E. 3,3’-Diindolylmethane, but not indole-3-carbinol, inhibits histone deacetylase activity in prostate cancer cells. Toxicol. Appl. Pharmacol. 2012; 263(3): 345-51.
  27. Semov A., Iourtchenco L., Liu L.F., Li S., Xu Y., Su X. et al. Diindolylmethane (DIM) selectively inhibits cancer stem cells. Biochem. Biophys. Res. Commun. 2012; 424(1): 45-51.
  28. Kong D., Sethi S., Li Y., Chen W., Sakr W.A., Heath E., Sarkar F.H. Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes. Prostate. 2015; 75(2): 161-74.
  29. Chen D., Banerjee S., Cui Q.C., Kong D., Sarkar F.H., Doi Q.P. Activation of AMP-activated protein kinase by 3,3’-diindolylmethane (DIM) is associated with human prostate cancer cell death in vitro and in vivo. PLoS One. 2012; 7(10): e47186.
  30. Castañon A., Tristram A., Mesher D., Powell N., Beer H., Ashman S. et al. Effect of diindolylmethane supplementation on low-grade cervical cytological abnormalities: double-blind, randomised, controlled trial. Br. J. Cancer. 2012; 106(1): 45-52.
  31. Патент на изобретение №2318510, РФ. Киселев В.И. Суппозитории вагинальные на основе 3,3’-дииндолилметана (метиндола). Заявлено 19.04.2006, опубл. 10.03.2008. [Patent for invention №2318510, the Russian Federation. Kiselev V.I. Vaginal suppositories based on 3,3’-diindolylmethane (metindole). Stated 19.04.2006, publ. 10.03.2008. (in Russian)]
  32. Ashrafian L., Sukhikh G., Kiselev V., Paltsev M., Drukh V., Kuznetsov I. et al. Double-blind randomized placebocontrolled multicenter clinical trial (phase IIa) on diindolylmethane’s efficacy and safety in the treatment of CIN: implications for cervical cancer prevention. EPMA J. 2015; 6: 25.
  33. Ашрафян Л.А., Сухих Г.Т., Киселев В.И., Пальцев М.А., Аполихина И.А., Друх В.М., Кузнецов И.Н., Муйжнек Е.Л., Андрианова Е.А. Исследование эффективности препарата Цервикон-ДИМ у пациенток с диагнозом CIN 1-2 степени. Вестник Российского научного центра рентгенорадиологии Минздрава России. 2015; 15(4): 28-39. [Ashrafyan L.A., Sukhikh G.T., Kiselev V.I., Paltsev M.A., Apolikhina I.A., Drukh V.M., Kuznetsov I.N., Muyzhnek E.L., Andrianova E.A. Study of the effectiveness of the drug Cervicon-DIM in patients with a diagnosis of CIN 1-2 degrees. Bulletin of the Russian Scientific Center for X-ray Radiology of the Ministry of Health of Russia. 2015; 15 (4): 28-39. (in Russian)]. Available at: http://vestnik-rncrr.ru/vestnik/v15/papers/ashrafyan_v15.htm.
  34. Сухих Г.Т., Ашрафян Л.А., Киселев В.И., Аполихина И.А., Мальцева Л.И., Сутурина Л.В., Селиванов С.П., Леонидова Т.Н., Цхай В.Б., Радзинский В.Е., Ордиянц И.М., Бебнева Т.Н., Евтушенко И.Д., Удут В.В., Кулагина Н.В., Баранов А.Н., Хасанов Р.Ш., Гурьева В.А., Шамина И.В., Карахалис Л.Ю. и др. Исследование эффективности и безопасности препарата на основе дииндолилметана у пациентов с цервикальной интраэпителиальной неоплазией (CIN1–2). Акушерство и гинекология. 2018; 9: 91-8. [Sukhikh G.T., Ashrafyan L.A., Kiselev V.I., Apolikhina I.A., Maltseva L.I., Suturina L.V., Selivanov S.P., Leonidova T.N., Tskhay V.B., Radzinsky V.E., Ordiyants I.M., Bebneva T.N., Evtushenko I.D., Udut V.V., Kulagina N.V., Baranov A.N., Khasanov R .Sh., Gurieva V.A., Shamina I.V., Karakhalis L.Yu. et al. Study of the efficacy and safety of the drug based on diindolylmethane in patients with cervical intraepithelial neoplasia (CIN1-2). Obstetrics and gynecology. 2018; 9: 91-8. (in Russian)]

Received 30.11.2018

Accepted 07.12.2018

About the Authors

Kiselev, Vsevolod I., MD, associate academician of the Russian Academy of Sciences, Deputy of director of the Institute of Gynecoloigy and Mammology of Academician
V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia.
117997, Russia, Moscow, Ac. Oparina str. 4.Tel.: +74955314444. E-mail: vkis10@mail.ru
Muyzhnek, Ekaterina L., candidate of biological science, science director of company “MiraxBioPharma”.
115054, Russia, Moscow, Valovaya str. 21/125. Tel.: +74957658787. E-mail: muyzhnekEL@ilmixgroup.ru
Ashrafyan, Lev A., MD, academician of the Russian Academy of Sciences, director of Institute of Gynecoloigy and Mammology of Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia.
117997, Russia, Moscow, Ac. Oparina str. 4. Tel.: +74955314444. E-mail: LevAA@yahoo.com
Sukhikh, Gennady T., MD, academician of the Russian Academy of Sciences, director of Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia. 117997, Russia, Moscow, Ac. Oparina str. 4. Tel.: +74955314444. E-mail: secretariat@oparina4.ru

For citation: Kiselev V.I., Muyzhnek E.L., Ashrafyan L.A., Sukhikh G.T. A new paradigm in cervical neoplasia progression: from fundamental knowledge to practical gynecology. Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2019; (1): 5-12. (in Russian)
http: // dx.doi.org/10.18565/aig.2019.1.5-12

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