Free radical oxidation and antioxidant defense in uterine myoma and endometrioid adenocarcinoma depending on its degree of differentiation

Purpose of the study. To evaluate the features of free radical oxidation (FRO) and the principal enzymatic and non-enzymatic links of antioxidant defense in proliferating tissues of benign myoma and malignant endometrioid adenocarcinoma (EA) with varying degrees of differentiation.

Patients and methods. Patients who received surgical treatment for EA (n = 42) and uterine myoma (n = 14) were examined. Patients with stage Ia (n = 26) and stage Ib (n = 16) of disease were selected. 16 patients had highly differentiated (G1) EA, 12 had moderately differentiated (G2) EA, and 14 had low-differentiated (G3) EA. The activity of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione transferase (GST), reduced glutathione (GSH), vitamins A and E, lipid peroxidation products diene conjugates (DC) and malondialdehyde (MDA) were determined colorimetrically in the tissues of EA, myoma and intact uterus.

Results. Compared with the level in intact tissue, SOD decreased by 3.2 times and GST increased by 2.7 times in myoma (p < 0.01). Similar changes were noted for EA G1 – on average by 5.3 times (p < 0.01) and also DC increased by 2.2 times (p < 0.05). In EA G2 tissue, SOD and GPx activities were lower than in the intact tissue, by 5.7 and 4.5 times, respectively (p < 0.05), and lower GST, GPx and GSH than in the EA G1, by 4.9, 8.9 and 1.6 times, respectively (p < 0.05 – p < 0.01). In EA G3 tissue, there was an increase in GSH, GPx and GST from 1.5 to 7.1 times (p < 0.05 – p < 0.01) and lipid peroxidation products by an average of 2.5 times (p < 0.05), as well as a decrease in vitamins A and E by 2.9 and 4.6 times, respectively (p < 0.05) compared with the intact tissue. The tissue of the EA G2 had a minimal level of activity of the GSH-dependent system.

Conclusion. The results reflect the differences in the mechanisms of proliferation regulation by FRO in myomas and in the EA tissue with changes in its differentiation. Knowledge of the characteristics of individual links in the regulation of FRO can play a certain role in the use of antioxidant therapy for benign or malignant tumors of the uterus.

1. Shatalova SV, Ulyanova EP, Moiseenko TI, Nepomnyaschaya EM, Kolesnikov EN, Duritskiy MN. Morphological and some immunohistochemical features of different histotypes of uterine body cancer. Modern problems of science and education. 2023;(5):14-14. (In Russ.). https://doi.org/10.17513/spno.32953

2. AlAshqar A, Lulseged B, Mason-Otey A, Liang J, Begum UAM, Afrin S et al. Oxidative Stress and Antioxidants in Uterine Fibroids: Pathophysiology and Clinical Implications. Antioxidants (Basel). 2023;12(4):807. https://doi.org/10.3390/antiox12040807

3. Afrin S, El Sabah M, Manzoor A, Miyashita-Ishiwata M, Reschke L, Borahay MA. Adipocyte coculture induces a pro-inflammatory, fibrotic, angiogenic, and proliferative microenvironment in uterine leiomyoma cells. Biochim Biophys Acta Mol Basis Dis. 2023;1869(1):166564. https://doi.org/10.1016/j.bbadis.2022.166564

4. Marin AG, Filipescu A, Petca A. The Role of Obesity in the Etiology and Carcinogenesis of Endometrial Cancer. Cureus. 2024;16(4):e59219. https://doi.org/10.7759/cureus.59219

5. Kit OI, Vodolazhsky DI, Kutilin DS, Moiseenko TI, Nikitin IS, Frantsiyants EM. Changes in expression of estrogen-regulatory genes in malignancy uterine tissues. Kubanskij nauchnyj medicinskij vestnik. 2016;157(2):84-90. (In Russ)

6. Rozenko LJa, Sidorenko JuS, Frantsiyants EM. Vliyaet li ob"em opuholi na sostoyanie antioksidantnoj zashchity organizma. Voprosy oncologii. 1999;45(5):538-541. (In Russ)

7. Heidari F., Rabizadeh S, Mansournia MA, Mirmiranpoor H, Salehi SS, Akhavan S et al. Inflammatory, oxidative stress and anti-oxidative markers in patients with endometrial carcinoma and diabetes. Cytokine. 2019;120:186-190. https://doi.org/10.1016/j.cyto.2019.05.007.

8. Misra HP, Fridovich I. The role of superoxide anion in the autooxidation of epinephrine and simple assay for SOD. J. Biol. Chem. 1972;247:3170-3175.

9. Korolyuk MA, Ivanova LI, Majorova IG, Tokarev VE. Metod opredeleniya aktivnosti katalazy. Laboratornoe delo. 1988;(1):16-19. (In Russ.)

10. Moin VP. A simple and specific method for determining the activity of glutathione peroxidase in erythrocytes. Laboratornoe delo. 1986;(12):724-726. (In Russ.)

11. Arutynyan AV, Dubinina EE, Zybina NN. Metody ocenki svobodnoradikal'nogo okisleniya i antioksidantnoj sistemy organizma. Guidelines. St. Petersburg: "Foliant" Publ.; 2000. 104 p. (In Russ.)

12. Chernyauskene RCh, Varshkyavichene ZZ, Gribauskas PS. Odnovremennoe fluorimetricheskoe opredelenie koncentracii vitaminov E i A v syvorotke krovi. Laboratornoe delo. 1984;(6):362-365. (In Russ.)

13. Kopylova TN. Novyj metod opredeleniya kon"yugirovannyh dienov v syvorotke krovi. In: Kletochnaya i subkletochnaya eksperimental'naya patologiya pecheni. 1982. 135. (In Russ.)

14. Surikova EI, Goroshinskaja IA, Nerodo GA, Frantsiyants EM, Malejko ML, Shalashnaja EV et al. Activity of redox-regulatory systems in the tumor and surrounding tissues in various histological types of tumors. Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry. 2016;10(4):335-340. https://doi.org/10.1134/S1990750816040089.

15. Fletcher NM, Saed MG, Abu-Soud HM, Al-Hendy A, Diamond MP, Saed GM. Uterine fibroids are characterized by an impaired antioxidant cellular system: potential role of hypoxia in the pathophysiology of uterine fibroids. J Assist Reprod Genet. 2013;30(7):969-74. https://doi.org/10.1007/s10815-013-0029-7.

16. Todorović A, Pejić S, Gavrilović L, Pavlović I, Stojiljković V, Popović N et al. Expression of Antioxidant Enzymes in Patients with Uterine Polyp, Myoma, Hyperplasia, and Adenocarcinoma. Antioxidants. 2019;8(4):97. https://doi.org/10.3390/antiox8040097.

17. Olson SL, Akbar RJ, Gorniak A, Fuhr LI, Borahay MA. Hypoxia in uterine fibroids: role in pathobiology and therapeutic opportunities. Oxygen (Basel). 2024;4(2):236-252. https://doi.org/10.3390/oxygen4020013.

18. Kennedy L, Sandhu JK, Harper ME, Cuperlovic-Culf M. Role of Glutathione in Cancer: From Mechanisms to Therapies. Biomolecules. 2020;10(10):1429. https://doi.org/10.3390/biom10101429.

19. Singh RR, Reindl KM. Glutathione S-Transferases in Cancer. Antioxidants. 2021; 10(5):701. https://doi.org/10.3390/antiox10050701.

20. Vašková J, Kočan L, Vaško L, Perjési P. Glutathione-Related Enzymes and Proteins: A Review. Molecules. 2023;28(3):1447. https://doi.org/10.3390/molecules28031447.

21. Checa-Rojas A, Delgadillo-Silva LF, Velasco-Herrera MDC, Andrade-Domínguez A, Gil J, Santillán O et al. GSTM3 and GSTP1: novel players driving tumor progression in cervical cancer. Oncotarget. 2018;9(31):21696-21714. https://doi.org/10.18632/oncotarget.24796.

22. Obukhova L, Kopytova T, Murach E, Shchelchkova N, Kontorshchikova C, Medyanik I. et al. Glutathione and Its Metabolic Enzymes in Gliomal Tumor Tissue and the Peritumoral Zone at Different Degrees of Anaplasia. Curr Issues Mol Biol. 2022;44(12):6439-6449. https://doi.org/10.3390/cimb44120439.

23. Lavudi K, Nuguri SM, Olverson Z, Dhanabalan AK, Patnaik S, Kokkanti RR. Targeting the retinoic acid signaling pathway as a modern precision therapy against cancers. Front Cell Dev Biol. 2023;11:1254612. https://doi.org/10.3389/fcell.2023.1254612.

24. Wierzbowska N, Olszowski T, Chlubek D, Kozłowski M, Cymbaluk-Płoska A. Vitamins in Gynecologic Malignancies. Nutrients. 2024;16(9):1392. https://doi.org/10.3390/nu16091392.

25. Hunsu VO, Facey COB, Fields JZ, Boman BM. Retinoids as Chemo-Preventive and Molecular-Targeted Anti-Cancer Therapies. Int J Mol Sci. 2021;22(14):7731. https://doi.org/10.3390/ijms22147731.

26. Yang CS, Luo P, Zeng Z, Wang H, Malafa M, Suh N. Vitamin E and cancer prevention: Studies with different forms of tocopherols and tocotrienols. Mol Carcinog. 2020;59(4):365-389. https://doi.org/10.1002/mc.23160.