350 rub
Journal Technologies of Living Systems №4 for 2023 г.
Article in number:
Activity of NAD(P)H-oxidoreductases and oxidative homeostasis in endometrial and cervical cancer
Type of article: scientific article
DOI: https://doi.org/10.18127/j20700997-202304-03
UDC: 577.29, 616-006.66
Authors:

E.V. Proskurnina1, M.V. Fedorova2, V.I. Voznesensky3, E.A. Sosnova4

1 Research Centre for Medical Genetics (Moscow, Russian)

2 Lomonosov Moscow State University (Moscow, Russian)

3 Pletnev Moscow City Clinical Hospital of the Moscow Department of Health (Moscow, Russia)

4 Sechenov First Moscow State Medical University
of the Ministry of Health of the Russian Federation (Sechenov University) (Moscow, Russia)

1 proskurnina@gmail.com, 2 theklazontag@yandex.ru, 3 vlad525@gmail.com, 4 sosnova_e_a@staff.sechenov.ru

Abstract:

Reactive oxygen species (ROS) play an important and controversial role in carcinogenesis. NAD(P)H-oxidoreductases are one of the main sites for the synthesis of intracellular ROS; however, the role of these sources of ROS has not been adequately studied.

The objective is to study the activity of cytochrome b5 reductase (CYB5R) and cytochrome P450 reductase (CYPOR), as well as to determine the activity of blood neutrophils and the antioxidant potential of plasma.

The developed technique for assessing the activity of NAD(P)H-oxidoreductases is based on kinetic lucigenin-enhanced chemiluminescence with the stimuli NADH and NADPH, which reflects the activity of CYB5R and CYPOR, respectively. In endometrial cancer, poorly differentiated adenocarcinomas were characterized by low activity of CYB5R and CYPOR, highly differentiated adenocarcinomas were characterized by moderate activity, activity, moderately differentiated adenocarcinomas were characterized by high activity. In cervical cancer, groups of low and high activity CYB5R and CYPOR can be distinguished, with the group of high activity being moderately differentiated adenocarcinomas, the group of low activity being poorly differentiated adenocarcinomas. In the blood, even with malignant tumors of the endometrium and cervical cancer, there is no change in the antioxidant capacity or activation of neutrophils.

The results obtained indicate a significant role of NAD(P)H-oxidoreductases in the biochemistry of human cancer, which makes it possible to use the indicators of their activity for diagnostics and prognosis.

Pages: 31-44
For citation

Proskurnina E.V., Fedorova M.V., Voznesensky V.I., Sosnova E.A. Activity of NAD(P)H-oxidoreductases and oxidative homeostasis in endometrial and cervical cancer. Technologies of Living Systems. 2023. V. 20. № 4. Р. 31-44. DOI: https://doi.org/10.18127/ j20700997-202304-03 (In Russian).

References
  1. Sarmiento-Salinas F.L., Perez-Gonzalez A., Acosta-Casique A., Ix-Ballote A., Diaz A., Trevino S., Rosas-Murrieta N.H., Millan-Perez-Pena L., Maycotte P. Reactive oxygen species: Role in carcinogenesis, cancer cell signaling and tumor progression. Life Sci. 2021. V. 284. P. 119942.
  2. Chizhov A.Ya., Pinayev S.K., Savin S.Z. Ekologicheski obuslovlennyy oksidativnyy stress kak faktor onkogeneza. Tekhnologii zhivykh sistem. 2012. T. 9. № 1. S. 47–53. (in Russian).
  3. Trojano G., Olivieri C., Tinelli R., Damiani G.R., Pellegrino A., Cicinelli E. Conservative treatment in early stage endometrial cancer: a review. Acta bio-medica : Atenei Parmensis. 2019. V. 90. № 4. P. 405–410.
  4. Olusola P., Banerjee H.N., Philley J.V., Dasgupta S. Human Papilloma Virus-Associated Cervical Cancer and Health Disparities. Cells. 2019. V. 8. № 6.
  5. Liou G.Y., Storz P. Reactive oxygen species in cancer. Free radical research. 2010. V. 44. № 5. P. 479–496.
  6. Beevi S.S., Rasheed M.H., Geetha A. Evidence of oxidative and nitrosative stress in patients with cervical squamous cell carcinoma. Clinica chimica acta; international journal of clinical chemistry. 2007. V. 375. № 1-2. P. 119–123.
  7. Kobayashi H. Potential scenarios leading to ovarian cancer arising from endometriosis. Redox report: communications in free radical research. 2016. V. 21. № 3. P. 119–126.
  8. Scutiero G., Iannone P., Bernardi G., Bonaccorsi G., Spadaro S., Volta C. A., Greco P., Nappi L. Oxidative Stress and Endometriosis: A Systematic Review of the Literature. Oxidative medicine and cellular longevity. 2017. V. 2017. P. 7265238.
  9. Elahian F., Sepehrizadeh Z., Moghimi B., Mirzaei S.A. Human cytochrome b5 reductase: structure, function, and potential applications. Critical reviews in biotechnology. 2014. V. 34. № 2. P. 134–143.
  10. Wisniewska A., Jagiello K., Mazerska Z. [NADPH-cytochrome P450 reductase, not only the partner of cytochrome P450]. Postepy biochemii. 2009. V. 55. № 3. P. 272–278.
  11. Lund R.R., Leth-Larsen R., Caterino T.D., Terp M.G., Nissen J., Laenkholm A.V., Jensen O.N., Ditzel H.J. NADH-Cytochrome b5 Reductase 3 Promotes Colonization and Metastasis Formation and Is a Prognostic Marker of Disease-Free and Overall Survival in Estrogen Receptor-Negative Breast Cancer. Molecular & cellular proteomics: MCP. 2015. V. 14. № 11. P. 2988–2999.
  12. Zwierello W., Maruszewska A., Nowak R., Kostrzewa-Nowak D., Tarasiuk J. DNA damage induced by NADPH cytochrome P450 reductase-activated idarubicin in sensitive and multidrug resistant MCF7 breast cancer cells. Pharmacological reports: PR. 2017. V. 69. № 1. P. 185–195.
  13. Baker M.A., Krutskikh A., Curry B.J., Hetherington L., Aitken R.J. Identification of cytochrome-b5 reductase as the enzyme responsible for NADH-dependent lucigenin chemiluminescence in human spermatozoa. Biology of reproduction. 2005. V. 73. № 2. P. 334–342.
  14. Rezende F., Prior K.K., Lowe O., Wittig I., Strecker V., Moll F., Helfinger V., Schnutgen F., Kurrle N., Wempe F., Walter M., Zukunft S., Luck B., Fleming I., Weissmann N., Brandes R. P., Schroder K. Cytochrome P450 enzymes but not NADPH oxidases are the source of the NADPH-dependent lucigenin chemiluminescence in membrane assays. Free radical biology & medicine. 2017. V. 102. P. 57–66.
  15. Mukaida N., Sasaki S.I., Baba V. Two-Faced Roles of Tumor-Associated Neutrophils in Cancer Development and Progression. Int. J. Mol. Sci. 2020. V. 21. № 10.
  16. Shen M., Hu P., Donskov F., Wang G., Liu Q., Du J. Tumor-associated neutrophils as a new prognostic factor in cancer: a systematic review and meta-analysis. PLoS One. 2014. V. 9. № 6. P. e98259.
  17. Hurt B., Schulick R., Edil B., El Kasmi K.C., Barnett C.,Jr. Cancer-promoting mechanisms of tumor-associated neutrophils. Am. J. Surg. 2017. V. 214. № 5. P. 938–944.
  18. Kovaleva O.V., Oleynikova N.A., Danilova N.V., Malkov P.G., Grachev A.N. Rol makrofagov. assotsiirovannykh s opukholyu. v progressii raka sheyki matki. Tekhnologii zhivykh sistem. 2017. T. 14. № 3. S. 4–12. (in Russian).
  19. Alekseyev A.V., Proskurnina E.V., Vladimirov Yu.A. Opredeleniye antioksidantov metodom aktivirovannoy khemilyuminestsentsii s ispolzovaniyem 2.2?-azo-bis(2-amidinopropana). Vestnik Moskovskogo un-ta. Ser. Khimiya. 2012. T. 53. № 3. S. 187–193. (in Russian).
  20. Obraztsov I.V., Godkov M.A., Polimova A.M., Demin E.M., Proskurnina E.V., Vladimirov Yu.A. Otsenka funktsionalnoy aktivnosti neytrofilov tselnoy krovi metodom dvukhstadiynoy stimulyatsii: novyy podkhod k khemilyuminestsentnomu analizu. Rossiyskiy immunologicheskiy zhurnal. 2015. T. 9 (18). № 4. S. 418–425. (in Russian).
  21. Haruma T., Nakamura K., Nishida T., Ogawa C., Kusumoto T., Seki N., Hiramatsu Y. Pre-treatment neutrophil to lymphocyte ratio is a predictor of prognosis in endometrial cancer. Anticancer Res. 2015. V. 35. № 1. P. 337–343.
  22. Kim B.W., Jeon Y.E., Cho H., Nam E.J., Kim S.W., Kim S., Kim Y.T., Kim J.H. Pre-treatment diagnosis of endometrial cancer through a combination of CA125 and multiplication of neutrophil and monocyte. J. Obstet. Gynaecol. Res. 2012. V. 38. № 1. P. 48–56.
  23. Ni L., Tao J., Xu J., Yuan X., Long Y., Yu N., Wu R., Zhang Y. Prognostic values of pretreatment neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in endometrial cancer: a systematic review and meta-analysis. Arch. Gynecol. Obstet. 2020. V. 301. № 1. P. 251–261.
  24. Abakumova V.V., Antoneeva, II, Gening V.P., Dolgova D.R., Gening S.O. [Phenotype of Peripheral Blood Neutrophils in the Initial Stage of Endometrial Cancer]. Tsitologiia. 2016. V. 58. № 1. P. 23–29.
  25. Cho H., Kim J.H. Multiplication of neutrophil and monocyte counts (MNM) as an easily obtainable tumour marker for cervical cancer. Biomarkers. 2009. V. 14. № 3. P. 161–170.
  26. Wang D., Wu M., Feng F.Z., Huang H.F., Yang J.X., Shen K., Xiang Y. Pretreatment neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios do not predict survival in patients with cervical cancer treated with neoadjuvant chemotherapy and radical hysterectomy. Chin. Med. J. (Engl). 2013. V. 126. № 8. P. 1464–1468.
  27. Escande A., Haie-Meder C., Maroun P., Gouy S., Mazeron R., Leroy T., Bentivegna E., Morice P., Deutsch E., Chargari P. Neutrophilia in locally advanced cervical cancer: A novel biomarker for image-guided adaptive brachytherapy? Oncotarget. 2016. V. 7. № 46. P. 74886–74894.
  28. Lee J.W., Seol K.H. Pretreatment Neutrophil-to-Lymphocyte Ratio Combined with Platelet-to-Lymphocyte Ratio as a Predictor of Survival Outcomes after Definitive Concurrent Chemoradiotherapy for Cervical Cancer. J. Clin. Med. 2021. V. 10. № 10.
  29. Matsumoto Y., Mabuchi S., Kozasa K., Kuroda H., Sasano T., Yokoi E., Komura N., Sawada K., Kimura V. The significance of tumor-associated neutrophil density in uterine cervical cancer treated with definitive radiotherapy. Gynecol. Oncol. 2017. V. 145. № 3. P. 469–475.
  30. Manju V., Kalaivani Sailaja J., Nalini N. Circulating lipid peroxidation and antioxidant status in cervical cancer patients: a case-control study. Clin. Biochem. 2002. V. 35. № 8. P. 621–625.
  31. Punnonen R., Kudo R., Punnonen K., Hietanen E., Kuoppala T., Kainulainen H., Sato K., Ahotupa M. Activities of antioxidant enzymes and lipid peroxidation in endometrial cancer. Eur. J. Cancer. 1993. V. 29A. № 2. P. 266–269.
  32. Gifkins D., Olson S. H., Demissie K., Lu S. E., Kong A. N., Bandera E. V. Total and individual antioxidant intake and endometrial cancer risk: results from a population-based case-control study in New Jersey. Cancer Causes Control. 2012. V. 23. № 6. P. 887–895.
  33. Villalba J.M., Navarro F., Gomez-Diaz C., Arroyo A., Bello R.I., Navas P. Role of cytochrome b5 reductase on the antioxidant function of coenzyme Q in the plasma membrane. Molecular aspects of medicine. 1997. V. 18 Suppl. P. S7–S13.
  34. Mahmutoglu I., Kappus H. Redox cycling of bleomycin-Fe(III) and DNA degradation by isolated NADH-cytochrome b5 reductase: involvement of cytochrome b5. Molecular pharmacology. 1988. V. 34. № 4. P. 578–583.
  35. Samhan-Arias A.K., Marques-da-Silva D., Yanamala N., Gutierrez-Merino P. Stimulation and clustering of cytochrome b5 reductase in caveolin-rich lipid microdomains is an early event in oxidative stress-mediated apoptosis of cerebellar granule neurons. Journal of proteomics. 2012. V. 75. № 10. P. 2934–2949.
  36. Bello R.I., Alcain F.J., Gomez-Diaz C., Lopez-Lluch G., Navas P., Villalba J.M. Hydrogen peroxide- and cell-density-regulated expression of NADH-cytochrome b5 reductase in HeLa cells. Journal of bioenergetics and biomembranes. 2003. V. 35. № 2. P. 169–179.
  37. Xiao X., Zhao W., Tian F., Zhou X., Zhang J., Huang T., Hou B., Du C., Wang S., Mo Y., Yu N., Zhou S., You J., Zhang Z., Huang G., Zeng X. Cytochrome b5 reductase 2 is a novel candidate tumor suppressor gene frequently inactivated by promoter hypermethylation in human nasopharyngeal carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2014. V. 35. № 4. P. 3755–3763.
  38. Ming H., Lan Y., He F., Xiao X., Zhou X., Zhang Z., Li P., Huang G. Cytochrome b5 reductase 2 suppresses tumor formation in nasopharyngeal carcinoma by attenuating angiogenesis. Chinese journal of cancer. 2015. V. 34. № 10. P. 459–467.
  39. Proskurnina E.V., Fedorova M.V., Sozarukova M.M., Mitichkin A.E., Panteleev I.V., Svetlov E.V. Microsomal reductase activity in patients with thyroid neoplasms. Endocrine. 2021. V. 72. № 3. P. 735–743.
  40. Shimamoto N. [A pathophysiological role of cytochrome p450 involved in production of reactive oxygen species]. Yakugaku zasshi: Journal of the Pharmaceutical Society of Japan. 2013. V. 133. № 4. P. 435–450.
  41. Pillai V.C., Snyder R.O., Gumaste U., Thekkumkara V.J., Mehvar R. Effects of transient overexpression or knockdown of cytochrome P450 reductase on reactive oxygen species generation and hypoxia reoxygenation injury in liver cells. Clinical and experimental pharmacology & physiology. 2011. V. 38. № 12. P. 846–853.
  42. Zangar R.C., Davydov D.R., Verma S. Mechanisms that regulate production of reactive oxygen species by cytochrome P450. Toxicology and applied pharmacology. 2004. V. 199. № 3. P. 316–331.
  43. Hrycay E.G., Bandiera S.M. Involvement of Cytochrome P450 in Reactive Oxygen Species Formation and Cancer. Advances in pharmacology. 2015. V. 74. P. 35–84.
Date of receipt: 13.09.2023
Approved after review: 20.09.2023
Accepted for publication: 20.10.2023