Cell Biochemistry and Biophysics

, Volume 77, Issue 1, pp 69–77 | Cite as

The Inhibiting Effect of Dinitrosyl Iron Complexes with Thiol-containing Ligands on the Growth of Endometrioid Tumours in Rats with Experimental Endometriosis

  • Evgeniya N. Burgovа
  • Yana I. Khristidis
  • Aleksandr V. Kurkov
  • Vasak D. Mikoyan
  • Anatoly B. Shekhter
  • Leila V. Adamyan
  • Peter S. Timashev
  • Anatoly F. VaninEmail author
Original Paper


The possibility that binuclear dinitrosyl iron complexes with glutathione and cysteine (DNIC-GSН and B-DNIC-Cys) have a strong cytotoxic effect on the growth of endometrioid tumours (EMT) in rats with surgically induced experimental endometriosis established in our previous studies has been supported with experimental data. The increase in the DNIC-GSН or B-DNIC-Cys dose from 10 (in our previous studies) to 20 μmol/kg (after i/p administration to experimental rats) fully suppressed the growth of uterine tissues implanted onto the inner surface of the abdominal wall. At 2 μmol/kg DNIC-GSН, the median value of EMT volume increased from 0 to 15 mm3, while the mean size of EMT—from 55 to 77 mm3 (data from EMT measurements in 10 experimental rats). After treatment of animals with B-DNIC with N-acetyl-L-cysteine (10 μmol/kg) known for its ability to penetrate easily through the cell membrane, the inhibiting effect on EMT growth diminished as could be evidenced from the transformation of ~30% of the implants into large-size EMT. Possible reasons for this phenomenon are discussed.


Dinitrosyl iron complexes Endometriosis Nitric oxide 


B- or M-DNIC

binuclear or mononuclear dinitrosyl iron complexes




endometrioid tumours


electron paramagnetic resonance




ribonucleotide reductase





This work has been carried out in the framework of the State Programs of the Russian Federal Agency for Scientific Organizations (0082-2014-0001, No. АААА-A17-117040610310-6 0082-2014-0008 and No. AAAA-A17-117040310008-5). The study is sponsored by Russian academic excellence project “5-100” and supported by the Russian Foundation for Fundamental Research (Grant No. 18-04-00059а) and the Russian Scientific Foundation (Grant No. 16-13-10295).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Burgova, E. N., Tkachev, N. A., Mikoyan, V. D., Adamyan, L. V., Stepanyan, A. A., & Vanin, A. F. (2014). Dinitrosyl iron complexes with glutathione suppress experimental endometriosis in rats. European Journal of Pharmacology, 727, 140–147.CrossRefPubMedGoogle Scholar
  2. 2.
    Burgova, E. N., Tkachev, N. A., Paklina, O. V., Mikoyan, V. D., Adamyan, L. V., & Vanin, A. F. (2014). The effect of dinitrosyl iron complexes with glutathione and S-nitrosoglutathione on the development of experimental endometriosis in rats: comparative studies. European Journal of Pharmacology, 741, 37–44.CrossRefPubMedGoogle Scholar
  3. 3.
    Vanin, A. F., Burgova, E. N., & Adamyan, L. V. (2015). Dinitrosyl iron complexes with glutathione suppress surgically induced experimental endometriosis in rats. Austin Journal of Reproductive Medicine & Infertility, 2, 1019–1031.CrossRefGoogle Scholar
  4. 4.
    Borodulin, R. R., Kubrina, L. N., Shvydkiy, V. О, Lakomkin, V. L., & Vanin, A. F. (2013). A simple protocol for the synthesis of dinitrosyl iron complexes with glutathione: EPR, optical, chromatographic and biological characterization of reaction products. Nitric Oxide: Biology and Chemistry, 35, 110–115.CrossRefGoogle Scholar
  5. 5.
    Vanin, A. F., Poltorakov, A. P., Mikoyan, V. D., Kubrina, L. N., & Burbaev, D. S. (2010). Polynuclear water-soluble dinitrosyl iron complexes with cysteine or glutathione ligands: electron paramagnetic resonance and optical studies. Nitric Oxide: Biology and Chemistry, 23, 1236–1249.Google Scholar
  6. 6.
    Vercellini, P., Crosignani, P. G., Abbiati, A., Somigliana, E., Vigano, P., & Fidele, L. (2009). The effect of surgery for symptomatic endometriosis: the other side of the story. Human Reproduction Update, 15, 177–188.CrossRefPubMedGoogle Scholar
  7. 7.
    Beinert, H., & Albracht, S. P. (1982). Iron–sulphur proteins. New insight and unresolved problems. Biochimica et Biophysica Acta (BBA) – Reviews on Bioenergetics, 683, 246–277.Google Scholar
  8. 8.
    Vanin, A. F., Serezhenkov, V. A., Mikoyan, V. D., & Genkin, M. V. (1998). The 2.03 signal as an indicator of dinitrosyl iron complexes with thiol-containing ligands. Nitric Oxide: Biology and Chemistry, 2, 224–234.CrossRefGoogle Scholar
  9. 9.
    Yonetany, T. (1999). Structural and functional regulation of hemoglobin by nitric oxide as studied by EPR spectroscopy. RIKEN Review, 24, 51–52.Google Scholar
  10. 10.
    Emanuel, N. M., Saprin, A. N., Shabalkin, V. A., Kozlova, L. E., & Kruglyakova, K. E. (1969). Detection and investigation of a new type of an ESR signal characteristic of some tumor tissues. Nature, 222, 162–167.CrossRefGoogle Scholar
  11. 11.
    Maruyama, T., Kataoka, N., Nagase, S., Nakada, H., Sato, H., & Sasaki, H. (1971). Identification of three-line electron spin resonance signal and its relationship to ascites tumors. Cancer Research, 31, 179–184.PubMedGoogle Scholar
  12. 12.
    Yurtaeva, S. V., Efimov, V. N., Silkin, N. I., Rodionov, A. A., Burmistrov, M. V., Panov, A. V., & Moroshek, A. A. (2012). Magnetic resonance of ferritin crystalline particles in tumor issues. Applied Magnetic Resonance, 42, 299–311.CrossRefGoogle Scholar
  13. 13.
    Fontecave, M. (1998). Ribonucleotide reductase and radical reactions. Cellular and Molecular Life Sciences, 54, 684–695.CrossRefPubMedGoogle Scholar
  14. 14.
    Chazov, E. I., Rodnenkov, O. V., Zorin, A. V., Lakomkin, V. L., Gramovich, V. V., Vyborov, O. V., Dragnev, A. G., Timodshin, A. A., Buryachkovskaya, L. I., Abramov, A. A., Massenko, V. P., Arzamastsev, E. V., Kapelko, V. I., & Vanin, A. F. (2012). Hypotensive effect of “Oxacom” containing a dinitrosyl iron complex with glutathione: animal studies and clinical trials on healthy volunteers. Nitric Oxide: Biology and Chemistry, 26, 148–157.CrossRefGoogle Scholar
  15. 15.
    Vanin, A. F. (2009). Dinitrosyl iron complexes with thiolate ligands: physico-chemistry, biochemistry, and physiology. Nitric Oxide: Biology and Chemistry, 21, 1–13.Google Scholar
  16. 16.
    Vanin, A. F. (2013). Dinitrosyl iron complexes with thiol-containing ligands as a base for new-generating drugs (review). The Open Conference Proceeding Journal, 4, 23–30.Google Scholar
  17. 17.
    Vanin, A. F. (2014). Dinitrosyl iron complexes with natural thiol-containing ligands: physico-chemistry, biology and medicine. In G. Jaonen, M. Salmain (Eds.), Bioorganometallic chemistry application in drug discovery, biocatalysis and imaging (pp. 203–238). Paris: Wiley Verlag.Google Scholar
  18. 18.
    Vanin, A. F. (2016). Dinitrosyl iron complexes with thiol-containinig ligands as a “working form” of endogenous nitric oxide. Nitric Oxide: Biology and Chemistry, 54, 16–29.Google Scholar
  19. 19.
    Lu, T.-T., Wang, Y.-M., Hung, C.-H., Chiou, S.-J., & Liaw, W.-F. (2018). Bioinorganic chemistry of the natural [Fe(NO)2] motif: evolution of a functional model for NO-related biomedical application and revolutionary development of a translational model. Inorganic Chemistry, 57, 12425–12443.CrossRefPubMedGoogle Scholar
  20. 20.
    Liu, T., Zhang, M., Terry, M. H., Schroeder, H., Wilson, S. M., Power, G. G., Li, Q., Tipple, T. E., Borchardt, D., & Blood, A. B. (2018). Hemodinamic effects of glutathione-liganded binuclear dinitrosyl iron complex: evidence for nitroxyl generation and modulation by plasma albumin. Molecular Pharmacology, 93, 427–437.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Borodulin, R. R., Kubrina, L. N., Mikoyan, V. D., Poltorakov, A. P., Shvydkiy, V. O., Burbaev, D. S., Serezhenkov, V. A., Yakhontova, E. R., & Vanin, A. F. (2013). Dinitrosyl iron co mplexes with glutathione as NO and NO+ donors. Nitric Oxide: Biology and Chemistry, 29, 4–16.Google Scholar
  22. 22.
    Kleschyov, A. L., Strand, S., Schmitt, S., Gottfried, D., Skatchkov, M., Sjakste, N., Daiber, A., Umansky, V., & Munzel, T. (2006). Dinitrosyl-iron triggers apoptosis in Jurkat cells despite overexpression of Bcl-2. Free Radical Biology and Medicine, 40, 1340–1348.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Evgeniya N. Burgovа
    • 1
  • Yana I. Khristidis
    • 2
  • Aleksandr V. Kurkov
    • 2
  • Vasak D. Mikoyan
    • 1
  • Anatoly B. Shekhter
    • 2
  • Leila V. Adamyan
    • 3
  • Peter S. Timashev
    • 2
  • Anatoly F. Vanin
    • 1
    • 2
    Email author
  1. 1.N.N. Semenov Institute of Chemical PhysicsRussian Academy of SciencesMoscowRussia
  2. 2.Institute of Regenerative MedicineI.M. Sechenov UniversityMoscowRussia
  3. 3.Reproductive Medicine and SurgeryMoscow University of Medicine and DentistryMoscowRussia

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