Changes in lipid peroxidation markers and antioxidant status depending on the stage of lung adenocarcinoma

In the present article, the dynamics of blood lipid peroxidation (LPO) markers and the antioxidant system (AOS) are investigated in patients with lung adenocarcinoma (LA) at different disease stages (I–IV). The study included 40 patients with histologically verified LA and 40 healthy donors. In blood serum, the concentrations of malondialdehyde (MDA), diene conjugates (DC), triene conjugates (TC), and Schiff bases (SB) were determined. In erythrocyte hemolysates, the activity of glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), and the level of reduced glutathione (GSH) were measured. In LA patients, a pronounced increase in LPO markers (MDA, DC, SB) and a decrease in GPx activity and GSH levels were revealed compared with the control group. A stage-dependent pattern was established: MDA levels were highest at stage I (a 3.4-fold increase), followed by a decline by stage IV. The concentration of DC (a primary LPO product) was elevated at the early stages, whereas secondary and terminal products (TC and SB) showed a progressive increase from stage I to stage IV (SB exceeding control values by 30.7-fold at stage IV). GPx activity was reduced at all stages, and GSH levels remained consistently decreased. GR activity exhibited a non-linear pattern. The development of lung adenocarcinoma is accompanied by a profound imbalance in pro-/antioxidant homeostasis, manifested by enhanced LPO and depletion of antioxidant defenses. A specific stage-related dynamics of LPO markers is demonstrated: a marked rise in primary and secondary products at early stages, followed by a shift in the marker profile at advanced stages. The antioxidant system displays a phased response, with signs of partial compensation at stage III and decompensation at stage IV of the disease.

1. Status Indicators of Lipid Peroxidation and Endogenous Intoxication in Lung Cancer Patients. / Belskaya L.V., Kosenok V.K., Massard Z. [et al.] // Annals of the Russian Academy of Medical Sciences. 2016;71(4):313–322. doi:10.15690/vramn712.

2. Aguilar Diaz De Leon R, Borges CR. Evaluation of oxidative stress in biological samples using the thiobarbituric acid reactive substances assay. J Vis Exp. 2020;(159):e61122. doi:10.3791/61122.

3. An X, Yu W, Liu J, Tang D, Yang L, Chen X. Oxidative cell death in cancer: mechanisms and therapeutic opportunities. Cell Death Dis. 2024;15:556. doi:10.1038/s41419-024-06939-5.

4. Barartabar Z, Moini N, Abbasalipourkabir R, Mesbah-Namin SA, Ziamajidi N. Assessment of tissue oxidative stress, antioxidant parameters, and zinc and copper levels in patients with breast cancer. Biol Trace Elem Res. 2023;201(7):3233-3244. doi:10.1007/s12011-022-03439-5.

5. Belskaya LV, Sarf EA, Kosenok VK, Gundyrev IA. Biochemical markers of saliva in lung cancer: diagnostic and prognostic perspectives. Diagnostics (Basel). 2020;10(4):186. doi:10.3390/diagnostics10040186.

6. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. doi:10.3322/caac.21834.

7. Cecerska-Heryć E, Krauze K, Szczęśniak A, et al. Activity of erythrocyte antioxidant enzymes in healthy women depends on age, BMI, physical activity, and diet. J Health Popul Nutr. 2022;41:35. doi:10.1186/s41043-022-00311-z.

8. Chaudhary P, Janmeda P, Docea AO, Yeskaliyeva B, Abdull Razis AF, Modu B, Calina D, Sharifi-Rad J. Oxidative stress, free radicals and antioxidants: potential crosstalk in the pathophysiology of human diseases. Front Chem. 2023;11:1158198. doi:10.3389/fchem.2023.1158198.

9. Deryugina AV, Danilova DA, Brichkin YD, et al. Molecular hydrogen exposure improves functional state of red blood cells in the early postoperative period: a randomized clinical study. Med Gas Res. 2023;13(2):59-66. doi:10.4103/2045-9912.356473.

10. Frankell AM, Dietzen M, Al Bakir M, et al. The evolution of lung cancer and impact of subclonal selection in tracerx. Nature. 2023;616:525-533. doi:10.1038/s41586-023-05783-5.

11. Frković M, Bobić J, Pape Medvidović E, et al. Erythrocyte glutathione s-transferase activity as a sensitive marker of kidney function impairment in children with iga vasculitis. Int J Mol Sci. 2024;25(7):3795. doi:10.3390/ijms25073795.

12. Gęgotek A, Nikliński J, Žarković N, Žarković K, Waeg G, Łuczaj W, et al. Lipid mediators involved in the oxidative stress and antioxidant defence of human lung cancer cells. Redox Biol. 2016;9:210-219. doi:10.1016/j.redox.2016.08.010.

13. Jomova K, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Valko M. Several lines of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities, and low-molecular-weight antioxidants. Arch Toxicol. 2024;98:1323-1367. doi:10.1007/s00204-024-03696-4.

14. Jomova K, Raptova R, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Valko M. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging. Arch Toxicol. 2023;97(10):2499-2574. doi:10.1007/s00204-023-03562-9.

15. Karasaki T, Moore DA, Veeriah S, et al. Evolutionary characterization of lung adenocarcinoma morphology in tracerx. Nat Med. 2023;29(4):833-845. doi:10.1038/s41591-023-02230-w.

16. Karki P, Birukov KG. Oxidized phospholipids in control of endothelial barrier function: mechanisms and implication in lung injury. Front Endocrinol (Lausanne). 2021;12:794437. doi:10.3389/fendo.2021.794437.

17. Krzystek-Korpacka M, Mierzchała-Pasierb M, Zawadzki M, Diakowska D, Witkiewicz W. Serum and erythrocyte antioxidant defense in colorectal cancer patients during early postoperative period: potential modifiers and impact on clinical outcomes. Antioxidants (Basel). 2021;10(7):999. doi:10.3390/antiox10070999.

18. Lei L, Zhang J, Decker EA, Zhang G. Roles of lipid peroxidation-derived electrophiles in pathogenesis of colonic inflammation and colon cancer. Front Cell Dev Biol. 2021;9:665591. doi:10.3389/fcell.2021.665591.

19. Li K, Deng Z, Lei C, Ding X, Li J, Wang C. The role of oxidative stress in tumorigenesis and progression. Cells. 2024;13(5):441. doi:10.3390/cells13050441.

20. Maddipati KR, Marnett LJ, et al. Avoiding spurious oxidation of glutathione during sample preparation and analysis of erythrocyte glutathione. J Lab Med. 2019;43(6):311-322. doi:10.1515/labmed-2019-xxxx.

21. Nakamura H, Takada K. Reactive oxygen species in cancer: current findings and future directions. Cancer Sci. 2021;112(10):3945-3952. doi:10.1111/cas.15068.

22. Ovchinnikov AN, Paoli A, Seleznev VV, Deryugina AV. Measurement of lipid peroxidation products and creatine kinase in blood plasma and saliva of athletes at rest and following exercise. J Clin Med. 2022;11(11):3098. doi:10.3390/jcm11113098.

23. Ovchinnikov AN, Paoli A, Seleznev VV, et al. Saliva as a diagnostic tool for early detection of exercise-induced oxidative damage in female athletes. Biomedicines. 2024;12(5):1006. doi:10.3390/biomedicines12051006.

24. Parkington DA, Koulman A, Jones KS. Protocol for measuring erythrocyte glutathione reductase activity coefficient to assess riboflavin status. STAR Protocols. 2023;4(4):102726. doi:10.1016/j.xpro.2023.102726.

25. Popova NN, Goroshinskaya IA, Shikhlyarova AI, et al. Parameters of free radical oxidation and antioxidant defense in patients with cervical cancer before and after radical surgical treatment. South Russian Journal of Cancer. 2023;4(2):28-38. doi:10.37748/2686-9039-2023-4-2-3.

26. Ramsden CE, Keyes GS, Calzada E, et al. Lipid peroxidation induced apoe receptor-ligand disruption as a unifying hypothesis underlying sporadic alzheimer’s disease in humans. J Alzheimers Dis. 2022;87(3):1251-1290. doi:10.3233/JAD-220071.

27. Richie-Jannetta R, Pallan P, Kingsley PJ, et al. The peroxidation-derived dna adduct, 6-oxo-m1dg, is a strong block to replication by human dna polymerase η. J Biol Chem. 2023;299(8):105067. doi:10.1016/j.jbc.2023.105067.

28. Sadžak A, Brkljača Z, Eraković M, Kriechbaum M, Maltar-Strmecki N, Přibyl J, Šegota S. Puncturing lipid membranes: onset of pore formation and the role of hydrogen bonding in the presence of flavonoids. J Lipid Res. 2023;64(10):100430. doi:10.1016/j.jlr.2023.100430.

29. Slika H, Mansour H, Wehbe N, et al. Therapeutic potential of flavonoids in cancer: ros-mediated mechanisms. Biomed Pharmacother. 2022;146:112442. doi:10.1016/j.biopha.2021.112442.

30. Uzel Şener M, Sönmez Ö, Keyf İA, et al. Evaluation of thiol/disulfide homeostasis in lung cancer. Turk Thorac J. 2020;21(4):255-260. doi:10.5152/TurkThoracJ.2019.19033.

31. Valgimigli L. Lipid peroxidation and antioxidant protection. Biomolecules. 2023;13(9):1291. doi:10.3390/biom13091291.

32. Wauchope OR, Mitchener MM, Beavers WN, et al. Oxidative stress increases m1dg, a major peroxidation-derived dna adduct, in mitochondrial dna. Nucleic Acids Res. 2018;46(7):3458-3467. doi:10.1093/nar/gky089.

33. Xiao L, Xian M, Zhang C, Guo Q, Yi Q. Lipid peroxidation of immune cells in cancer. Front Immunol. 2024;14:1322746. doi:10.3389/fimmu.2023.1322746.

34. Zhang Y, Vaccarella S, Morgan E, et al. Global variations in lung cancer incidence by histological subtype in 2020: a population-based study. Lancet Oncol. 2023;24(11):1206-1218. doi:10.1016/S1470-2045(23)00444-8.

35. Zheng Y, Sun J, Luo Z, Li Y, Huang Y. Emerging mechanisms of lipid peroxidation in regulated cell death and its physiological implications. Cell Death Dis. 2024;15:859. doi:10.1038/s41419-024-07244-x.