INVESTIGATION OF THE EFFICACY OF INDOLE-3-CARBINOL ON A RAT MODEL OF ENDOMETRIOSIS (EXPERIMENTAL STUDY)


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Abstract

Objective. To investigate the pharmacological activity of a drug with the active substance indole-3-carbinol on a rat model of endometriosis. Materials and methods. An experiment was carried out on on pubertal female rats (n = 60). According to pathology modeling and therapy, the animals were divided into groups. Group 1 consisted of falsely operated animals receiving starch solution. Group 2 included falsely operated ones given indole-3-carbinol at a dose of111 mg/kg. In Groups 3 to 5, endometriosis was modelled by autologous transplantation of endometrial tissue into the peritoneal cavity. Group 3 animals received 1% starch solution; Groups 4 and 5 had the active substance at doses of 37 and 111 mg/kg, respectively. Reactions to pain were studied in the animals and implants were also histologically assessed at 30 and 60 days. Results. The untreated animals with induced pathology showed a more pronounced pain response than falsely operated animals. Histological estimation revealed that endometrial hyperplasia tended to reduce in the groups of females that had received the active substance compared with that in the control groups. Conclusion. The investigation showed that indole-3-carbinol administered to the animals effectively decreased the size of an endometrioid focus and the degree of endometrioid heterotopies, thereby indicating the therapeutic effect on endometriosis-induced pain syndrome.

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About the authors

Vsevolod I. KISELEV

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia

Email: vkisl0@mail.ru
Doctor of Biological Sciences, Professor, Corresponding Member of RAS Professor, Deputy Director if the Institute of Oncogynecology and Mammology Moscow, Russia

Levon A. ASHRAFYAN

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia

Email: levaa2004@yahoo.com
DM, Professor, Academician of the Russian Academy of Sciences, Director оf the Institute of Oncogynecology and Mammology Moscow, Russia

Stanislav M. PRONIN

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia

Email: s_pronin@oparina4.ru
MD, PhD, Oncologist, Senior scientific researcher at the Institute of Oncogynecology and Mammology Moscow, Russia

Evgeniya V. GERFANOVA

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia

Email: e_gerfanova@oparina4.ru
MD, Oncologist at the Institute of Oncogynecology and Mammology Moscow, Russia

Igor N. KUZNETSOV

Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia

Email: i_kuznetsov@oparina4.ru
PhD, Deputy Director if the Institute of Oncogynecology and Mammology Moscow, Russia

Vadim M. DRUKH

AO «MiraxBioPharma»

Email: info@mbpharma.ru
DM, General Director Moscow, Russia

Vladimir V. UDUT

Tomsk National Research Medical Center

Email: udutv@mail.ru
DM, Professor, Corresponding Member of RAS, Deputy Director of Scientific and Medical Work, Head of the Laboratory of Physiology, Molecular and Clinical Pharmacology Research Institute of Pharmacology and Regenerative Medicine named after E.D. Goldberg Tomsk, Russia

Alexey A. CHURIN

Tomsk National Research Medical Center

Email: churin_aa@pharmso.ru
DM, Head of the Department of Drug Toxicology, Research Institute of Pharmacology and Regenerative Medicine named after E.D. Goldberg Tomsk, Russia

Olga I. PCHELINTSEVA

AO «MiraxBioPharma»

Email: pchelintseva87@mail.ru
MSc, Clinical trial manager Moscow, Russia

References

  1. Маржевская В.В., Присяжная Т.С., Жамойдик В.И., Берлев И.В., Малек А.В. Молекулярно-генетические основы эндометриоза: диагностический потенциал наследуемых и экспрессируемых факторов. Журнал акушерства и женских болезней. 2018; 67(3): 64-73.
  2. Адамян Л.В., ред. Клинические рекомендации по ведению больных. Эндометриоз: диагностика, лечение и реабилитация. М.; 2013.
  3. Zhou W.J., Yang H.L., Shao J., Mei J., Chang K.K., Zhu R., Li M.Q. Antiinflammatory cytokines in endometriosis. Cell. Mol. Life Sci. 2019; 76(11): 2111-32. https://dx.doi.org/10.1007/s00018-019-03056-x.
  4. Bulun S.E., Monsivais D., Kakinuma T., Furukawa Y., Bernardi L., Pavone M.E., Dyson M. Molecular biology of endometriosis: from aromatase to genomic abnormalities. Semin. Reprod. Med. 2015; 33(3): 220-4. https://dx.doi. org/10.1055/s-0035-1554053.
  5. Donnez J. Introduction: From pathogenesis to therapy, deep endometriosis remains a source of controversy. Fertil. Steril. 2017; 108(6): 869-71. https:// dx.doi.org/10.1016/j.fertnstert.2017.10.015.
  6. Киселев В.И., Пальцев М.А. Регуляция активности генов и новые лекарственные средства. Вестник Российской академии наук. 2016; 86(6): 512-8.
  7. Clemenza S., Sorbi F., Noci I., Capezzuoli T., Turrini I., Carriero C. et al. From pathogenesis to clinical practice: Emerging medical treatments for endometriosis. Best Pract. Res. Clin. Obstet. Gynaecol. 2018; 51: 92-101. https://dx.doi. org/10.1016/j.bpobgyn.2018.01.021.
  8. Aggarwal B.B., Ichikawa H. Molecular targets and anticancer potential of indole- 3-carbinol and its derivatives. Cell Cycle. 2005; 4(9): 1201-15. https://dx.doi. org/10.4161/cc.4.9.1993.
  9. Fujioka N., Fritz V., Upadhyaya P., Kassie F., Hecht S.S. Research on cruciferous vegetables, indole-3-carbinol, and cancer prevention: A tribute to Lee W. Wattenberg. Mol. Nutr. Food Res. 2016; 60(6): 1228-38. https://dx.doi. org/10.1002/mnfr.201500889.
  10. Cover C.M., Hsieh S.J., Cram E.J., Hong C., Riby J.E., Bjeldanes L.F., Firestone G.L. Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. Cancer Res. 1999; 59(6): 1244-51.
  11. Ampofo E., Schmitt B.M., Menger M.D., Laschke M.W. Targeting the Microcirculation by indole-3-carbinol and its main derivate 3,3,’-diindolylmethane: effects on angiogenesis, thrombosis and inflammation. Mini Rev. Med. Chem. 2018; 18(11): 962-8. https://dx.doi.org/10.2174/13895 57518666180313100144.
  12. Rahman K.M., Aranha O., Sarkar F.H. Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in nontumorigenic breast epithelial cells. Nutr. Cancer. 2003; 45(1): 101-12.
  13. Feitelson M.A., Arzumanyan A., Kulathinal R.J., Blain S.W., Holcombe R.F., Mahajna J. et al. Sustained proliferation in cancer: mechanisms and novel therapeutic targets. Semin. Cancer Biol. 2015; 35(Suppl.): S25-54. https://dx.doi.org/10.1016/j.semcancer.2015.02.006.
  14. Fuentes F., Paredes-Gonzalez X., Kong A.N. Dietary glucosinolates sulforaphane, phenethyl isothiocyanate, indole-3-carbinol/3,3’-diindolylmethane: antioxidative stress/inflammation, Nrf2, epigenetics/epigenomics and in vivo cancer chemopreventive efficacy. Curr. Pharmacol. Rep. 2015; 1(3): 179-96. https:// dx.doi.org/10.1007/s40495-015-0017-y.
  15. Ahmad A., Sakr W.A., Rahman K.W. Mechanisms and therapeutic implications of cell death induction by indole compounds. Cancers (Basel). 2011; 3(3): 2955-74. https://dx.doi.org/10.3390/cancers3032955.
  16. 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. https://dx.doi.org/10.1155/2014/832161.
  17. Wang S.Q., Cheng L.S., Liu Y., Wang J.Y., Jiang W. Indole-3-carbinol (I3C) and its major derivatives: their pharmacokinetics and important roles in hepatic protection. Curr. Drug Metab. 2016; 17(4): 401-9. https://dx.doi.org/10.2174/ 1389200217666151210125105.
  18. Riby J.E., Firestone G.L., Bjeldanes L.F. 3,3’-diindolylmethane reduces levels of HIF-1alpha and HIF-1 activity in hypoxic cultured human cancer cells. Biochem. Pharmacol. 2008; 75(9): 1858-67. https://dx.doi.org/10.1016/j. bcp.2008.01.017.
  19. Augoulea A., Alexandrou A., Creatsa M., Vrachnis N., Lambrinoudaki I. Pathogenesis of endometriosis: the role of genetics, inflammation and oxidative stress. Arch. Gynecol. Obstet. 2012; 286(1): 99-103. https://dx.doi.org/10.1007/ s00404-012-2357-8.
  20. Киселев В.И., Сметник В.П., Сутурина Л.В., Селиванов С.П., Рудакова Е.Б., Рахматуллина И.Р., Андреева Е.Н., Фадеева Н.И., Хасанов Р.Ш., Кулагина Н.В., Рожкова Н.И., Артымук Н.В., Гависова А.А., Муйжнек Е.Л., Кузнецов И.Н., Друх В.М. Индолкарбинол (Индинол Форто) - метод мультитаргетной терапии при циклической мастодинии. Акушерство и гинекология. 2013; 7: 56-62.
  21. Anesthesia and analgesia in laboratory animals at UCSF. The Regents of the University of California. Электронный ресурс: Available at: http://www.iacuc. ucsf.edu/Proc/awRbtFrm.asp Accessed 01.2019.
  22. Keenan J.A., Williams-Boyce P.K., Massey P.J., Chen T.T., Caudle M.R., Bukovsky A. Regression of endometrial explants in a rat model of endometriosis treated with the immune modulators loxoribine and levamisole. Fertil. Steril. 1999; 72(1): 135-41. https://dx.doi.org/10.1016/s0015-0282(99)00157-0.
  23. Tosti C., Biscione A., Morgante G., Bifulco G., Luisi S., Petraglia F. Hormonal therapy for endometriosis: from molecular research to bedside. Eur. J. Obstet. Gynecol. Reprod. Biol. 2017; 209: 61-6. https://dx.doi.org/10.1016/j. ejogrb.2016.05.032.
  24. Simmen R.C., Kelley A.S. Reversal of fortune: estrogen receptor-ß in endometriosis. J. Mol. Endocrinol. 2016; 57(2): F23-7. https://dx.doi. org/10.1530/JME-16-0080.
  25. ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin. Medical management of endometriosis. Number 11, December 1999 (replaces Technical Bulletin Number 184, September 1993). Clinical management guidelines for obstetrician gynecologists. Int. J. Gynaecol. Obstet. 2000; 71(2): 183-96. https://dx.doi.org/10.1016/s0020-7292(00)80034-x.
  26. Shertzer H.G., Senf A.P. The micronutrient indole-3-carbinol: implications for disease and chemoprevention. Drug Metabol. Drug Interact. 2000; 17(1-4): 159-88. https://dx.doi.org/ 10.1515/dmdi.2000.17.1-4.159.
  27. Rogan E.G. The natural chemopreventive compound indole-3-carbinol: state of the science. In Vivo. 2006; 20(2): 221-8.
  28. Тихончук Е.Ю., Асатурова А.В., Адамян Л.В. Частота выявления и структура патологических изменений эндометрия у женщин репродуктивного возраста с генитальным эндометриозом. Акушерство и гинекология. 2016; 12: 87-95.
  29. Ищенко А.И., Кудрина Е.А. Эндометриоз: диагностика и лечение. М.: ГЭОТАР-МЕД; 2002. 104 с.
  30. Ahmad A., Biersack B., Li Y., Kong D., Bao B., Schobert R. et al. Targeted regulation of PI3K/Akt/mTOR/NF-kB signaling by indole compounds and their derivatives: mechanistic details and biological implications for cancer therapy. Anticancer Agents Med. Chem. 2013; 13(7): 1002-13. https://dx.doi. org/10.2174/18715206113139990078.
  31. Wang X., He H., Lu Y., Ren W., Teng K.Y., Chiang C.L. et al. Indole-3-carbinol inhibits tumorigenicity of hepatocellular carcinoma cells via suppression of microRNA-21 and upregulation of phosphatase and tensin homolog. Biochim. Biophys. Acta. 2015; 1853(1): 244-53. https://dx.doi.org/10.1016/j. bbamcr.2014.10.017.
  32. Marconett C.N., Singhal A.K., Sundar S.N., Firestone G.L. Indole-3-carbinol disrupts estrogen receptor-alpha dependent expression of insulin-like growth factor-1 receptor and insulin receptor substrate-1 and proliferation of human breast cancer cells. Mol. Cell. Endocrinol. 2012; 363(1-2): 74-84. https://dx.doi. org/10.1016/j.mce.2012.07.008.

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