Effect of Bee Venom and Hyperthermia on Hepatic Lipid Peroxidation and Superoxide Dismutase Activity in Tumor-Bearing Animals

The search for low-toxicity drugs with high therapeutic efficacy remains a critical challenge in cancer therapy. This study aimed to evaluate the effect of bee venom combined with hyperthermia on lipid peroxidation (LPO) product levels and superoxide dismutase (SOD) activity in the liver homogenate of tumor-bearing rats. The experiment used RS-1 tumor-bearing rats. The study examined the effects of bee venom combined with hyperthermia at 42°С and 43°С. Comparison groups included untreated tumor-bearing rats and those subjected to hyperthermia (42°С or 43°С) or bee venom. Intact animals were used to establish the physiological norm. Liver tissue samples were collected on days 1, 7, and 14 post-treatment. The LPO product levels were assessed by measuring diene conjugates (DC), triene (TC) conjugates, and Schiff bases (SB) via spectrophotometry. The status of the antioxidant system was evaluated by analyzing SOD activity, also determined spectrophotometrically. The study demonstrated a reduction in LPO products in the liver homogenates of tumor-bearing rats following the combined application of hyperthermia and bee venom. By day 14, the combination of 43°C hyperthermia and bee venom resulted in a decrease in DC, TC, and SB relative to the control group, reaching the values observed in intact animals. With 42°С hyperthermia and bee venom, the reduction in these markers was less pronounced. Hyperthermia monotherapy proved ineffective, as the levels of the studied parameters continued to rise, consistent with the trends observed in the tumor-bearing control group. Hepatic SOD activity in tumor-bearing rats increased across all observation periods, with the most significant elevation occurring under 43°С hyperthermia. The combined use of hyperthermia and bee venom exerts a beneficial synergistic effect.

1. Volchegorsky I.A., Nalimov A.G., Yarovinsky B.G., Lifshits R.I. Sopostavleniye razlichnykh podkhodov k opredeleniyu produktov perekisnogo okisleniya lipidov v geptan-izopropanol'nykh ekstraktakh krovi [Comparison of different approaches to the determination of lipid peroxidation products in heptane-isopropanol blood extracts]. Voprosy meditsinskoy khimii [Questions of medicinal chemistry]. 1989;35(1):127–131. (In Russian).

2. Deryugina A.V., Shumilova A.V. Vliyaniye tsitoflavina na okislitel'nyy stress i aktivnost' Na/K-ATFazy eritrotsitov posle cherepno-mozgovoy travmy [Effect of cytoflavin on oxidative stress and erythrocyte Na/K-ATPase activity after traumatic brain injury]. S.S. Korsakov Journal of Neurology and Psychiatry. 2017;11(117):51–55. (In Russian).

3. Krasnikova O.V., Smetanina O.A., Kondrashina O.V., Shabalin M.A., Deryugina A.V., Khomutov A.E. Vliyaniye pchelinogo yada na sostoyaniye tkaney parodonta [The influence of bee venom on the condition of periodontal tissues]. Nauchnyye vedomosti Belgorodskogo gosudarstvennogo universiteta. Seriya: Meditsina. Farmatsiya [Scientific Bulletins of Belgorod State University. Series: Medicine. Pharmacy]. 2019;42(2):235–243. (In Russian).

4. Kseiko D.A., Gening T.P. Protsessy perekisnogo okisleniya lipidov i zashchitnaya rol' antioksidantnoy sistemy v pecheni i eritrotsitakh v usloviyakh ostroy krovopoteri [Processes of lipid peroxidation and the protective role of the antioxidant system in the liver and erythrocytes in conditions of acute blood loss]. Fundamental'nyye issledovaniya [Basic research]. 2012;(9-2):304–307. (In Russian).

5. Kuzmenko D.B., Lukyanov I.B., Efremov A.V., Lukyanova E.S. Vyzhivayemost' krys s kartsinosarkomoy Walker-256 pri vozdeystvii obshchey gipertermii [Survival of rats with Walker-256 carcinosarcoma when exposed to general hyperthermia]. Meditsina i obrazovaniye v Sibiri [Medicine and education in Siberia]. 2013;1:30. (In Russian).

6. Moskvicheva L.I., Bolotina L.V. Vozmozhnosti khimioterapii u bol'nykh mestnorasprostranennym i metastaticheskim adenogennym rakom podzheludochnoy zhelezy [Possibilities of chemotherapy in patients with locally advanced and metastatic adenogenic pancreatic cancer]. Issledovaniya i praktika v meditsine [Research and practice in medicine]. 2020;4(7):118–134. (In Russian).

7. Ovchinnikov A.N., Deryugina A.V. Rotovaya zhidkost' kak vysokoinformativnyy substrat neinvazivnogo issledovaniya protsessov lipoperoksidatsii i povrezhdeniya myshechnoy tkani u vysokokvalifitsirovannykh sportsmenov v usloviyakh fizicheskikh nagruzok [Oral fluid as a highly informative substrate for non-invasive research into the processes of lipid peroxidation and damage to muscle tissue in highly qualified athletes under conditions of physical activity]. Clinical laboratory diagnostics. 2019;7(64):405–408. (In Russian).

8. Popovich I.G., Anisimov V.N. Geroprotektory i kantserogenez [Geroprotectors and carcinogenesis]. Obzory po klinicheskoy farmakologii i lekarstvennoy terapii [Reviews on clinical pharmacology and drug therapy]. 2004;1(3):61–69. (In Russian).

9. Svetitsky P.V. Ispol'zovaniye tepla v lechenii zlokachestvennykh opukholey [Use of heat in the treatment of malignant tumors]. V kn.: Rak [In the book: Cancer]. Rostov-on-Don: Everest Publ., 2001:160. (In Russian).

10. Araújo A.M., Enea M., Carvalho F., Bastos M.L., Carvalho M., Guedes de Pinho P. Hepatic Metabolic Derangements Triggered by Hyperthermia: An In Vitro Metabolomic Study. Metabolites. 2019;9(10):228.

11. Bloomer S.A., Brown K.E., Buettner G.R., Kregel K.C. Dysregulation of hepatic iron with aging: implications for heat stress-induced oxidative liver injury. Am. J. of Physiology. 2008;294(4):1165–1174.

12. Chang D., Lim M., Goos J.A., Qiao R., Ng Y., Mansfeld F.M., Jackson M., Davis T.P., Kavallaris M. Biologically Targeted Magnetic Hyperthermia: Potential and Limitations. Front. Pharmacol. 2018;9:20.

13. Danilova D.A., Brichkin Yu.D., Medvedev A.P., Pichugin V.V., Fedorov S.A., Taranov E.V., Nazarov E.I., Ryazanov M.V., Bolshukhin G.V., Deryugina A.V. Application of molecular hydrogen in heart surgery under cardiopulmonary bypass. Modern technologies in medicine. 2021;13(1):71–77.

14. Deryugina A.V., Shumilova A.V., Filippenko E.S., Galkina Y.V., Simutis I.S., Boyarinov G.A. Functional and biochemical parameters of erythrocytes during mexicor treatment in posttraumatic period after experimental blood loss and combined traumatic brain injury. Bulletin of Experimental Biology and Medicine. 2017;1(164):26–29.

15. Elkomy A., El-Hanoun A., Abdella M., El-Sabrout K. Improving the reproductive, immunity and health status of rabbit does using honey bee venom. Anim. Physiol. Anim. Nutr. 2021;105(5):975–983.

16. Ferlay J., Ervik M., Lam F., Colombet M., Mery L., Piñe-ros M., et al. Global Cancer Observatory: Cancer Today. Lyon: International Agency for Research on Cancer, 2020.

17. Kangari P., Farahany Z., Golchin A., Ebadollahzadeh S., Salmaninejad A., Mahboob A., Nourazarian A. Enzymatic Antioxidant and Lipid Peroxidation Evaluation in the Newly Diagnosed Breast Cancer Patients in Iran. Asian Pac. J. Cancer Prev. 2018;19(12):3511–3515.

18. Kim J., Jang H., Leem J., Kim G. Protective Effects of Bee Venom-Derived Phospholipase A2 against Cholestatic Liver Disease in Mice. Biomedicines. 2021;9(8):992.

19. Kim W., An H., Kim J., Gwon M., Gu H., Lee S., Park J., Park K., Han S., Kim M., Park K. Apamin inhibits TNF-α- and IFN-γ-induced inflammatory cytokines and chemokines via suppressions of NF-κB signaling pathway and STAT in human keratinocytes. Pharmacol. Rep. 2017;69(5):1030–1035.

20. Luzhin A., Avanesyan B., Velichko A., Shender V., Ovsyannikova N., Arapidi G., Shnaider P., Petrova N., Kireev I., Razin S., Kantidze O. Chromatin Trapping of Factors Involved in DNA Replication and Repair Underlies Heat-Induced Radio- and Chemosensitization. Cells. 2020;9(6):1423.

21. Mahmoudi K., Bouras A., Bozec D., Ivkov R., Hadjipanayis C. Magnetic hyperthermia therapy for the treatment of glioblastoma: a review of the therapy’s history, efficacy and application in humans. Int. J. of Hyperthermia. 2018;8(34):1316–1328.

22. Mansour G.H., El-Magd M.A., Mahfouz D.H., Abdelhamid I.A., Mohamed M.F., Ibrahim N.S., Hady A., Abdel Wahab A., Elzayat E.M. Bee venom and its active component Melittin synergistically potentiate the anticancer effect of Sorafenib against HepG2 cells. Bioorganic Chemistry. 2021;116:1–13.

23. Martinello M., Mutinelli F. Antioxidant Activity in Bee Products: A Review. Antioxidants (Basel). 2021;10(1):71.

24. Mimoun N., Bahu M.V., Bukhekem S., Marouf N.U., Kelef D., Kaidi R. Cancer. J. of Siberian Medical Sciences. 2021;(2):77–103.

25. Moise S., Byrne J., El Haj A., Telling N. The potential of magnetic hyperthermia for triggering the differentiation of cancer cells. Royal Society of Chemistry. 2018;10:519–525.

26. Mortezaee K., Narmani A., Salehi M., Bagheri H., Farhood B., Haghi-Aminjanh H., Najafi M. Synergic effects of nanoparticles-mediated hyperthermia in radiotherapy. Сhemotherapy of Cancer Life Sciences. 2015;(269):119020.

27. Oršolić N. Bee venom in cancer therapy. Cancer Metastasis Rev. 2012;31(1-2):173–194.

28. Prasad S., Srivastava S. Oxidative stress and cancer: chemopreventive and therapeutic role of triphala. Antioxidants. 2020;9(1):72.

29. Salama M.A., Younis M.A., Talaat R.M. Cytokine and inflammatory mediators are associated with cytotoxic, anti-inflammatory and apoptotic activity of honeybee venom. J. Complement Integr. Med. 2020;18(1):75–86.

30. Somwongin S., Chantawannak P., Chaiyana W. Antioxidant activity and irritation property of venoms from Apis species. Toxicon. 2018;(145):32–39.

31. Waller L.P., Deshpande V., Pyrsopoulos N. Hepatocellular carcinoma: A comprehensive review. World J. Hepatol. 2015;7(26):2648–2663.

32. Yohsuke Y., Keishi T., Yasunobu K., Masakazu Y. Cancer immunity and therapy using hyperthermia with immunotherapy, radiotherapy, chemotherapy, and surgery. J. Cancer Metastasis Treat. 2017;3:218–230.