ANTIOXIDANT, METABOLIC AND ANTITUMOR ACTIVITY OF TRITERPENOIDS COMBINATION WITH CYTOSTATICS
Objective: To study the effect of betulin derivatives combination with 5-fluorouracil or hydrazine sulfate on the ROS generation, the SOD and LDH activity using rat blood, as well as the effect of combination drugs on Ehrlich carcinoma in experiments on mice.
Methods: We used a chemiluminescence technique to study the ROS generation, and spectrophotometry to determine the MDA level and the SOD and LDH activity. The model of transplanted Ehrlich ascites carcinoma was investigated on mice using a cytological analysis of ascitic fluid cells according to Pappenheim`s method.
Results: In vitro experiments on rat blood at the doses of 2, 5 and 10 μg per ml revealed the dose-dependent effect of combination drugs on the antioxidant properties. In plasma, the ROS generation and the MDA level increased by 10-300% in comparison with control at the doses of 5 and 10 μg per ml only. Still, the SOD and LDH activity in general increased by 10-130% in comparison with control under the action of the studied combination drugs. The study on mice showed the effectiveness of a combination of triterpenoids and cytostatics in Ehrlich ascites carcinoma therapy. The state and behavior of the animals improved, the volume of ascites fluid decreased by 40-50% after treatment for 10 d.
Conclusion: The combination of betulin derivatives with cytostatics can be used as antitumor drugs in Ehrlich ascites carcinoma therapy that is due to metabolic plasticity, increased ROS generation in enhanced antioxidant enzyme protection.
2. Perez J, Shen C-chang, Ragasa CY. Triterpenes from Ceriops decandra (Griff.) W. Theob. AJPCR 2017;10:244-6.
3. Evanjaline M, Vr M. Determination of bioactive components of Caralluma umbellata haw. (Apocynaceae) by gas chromatography and mass spectroscopy analysis. AJPCR 2018;11:194-9.
4. Hordyjewska A, Ostapiuk A, Horecka A. Betulin and betulinic acid in cancer research. J Pre-Clin Clin Res 2018;12:72-5.
5. Periasamy G, Teketelew G, Gebrelibanos M, Sintayehu B, Gebrehiwot M, Karim A, et al. Betulinic acid and its derivatives as an anti-cancer agent: a review. Arch Appl Sci Res 2014;6:47-58.
6. Bishayee A, Ahmed S, Brankov N, Perloff M. Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer. Front Biosci (Landmark Ed) 2011;16:980–96.
7. Parikh NR, Mandal A, Bhatia D, Siveen KS, Sethi G, Bishayee A. Oleanane triterpenoids in the prevention and therapy of breast cancer: current evidence and future perspectives. Phytochem Rev 2014;13:793–810.
8. Wei J, Liu H, Liu M, Wu N, Zhao J, Xiao L, et al. Oleanolic acid potentiates the antitumor activity of 5-fluorouracil in pancreatic cancer cells. Oncol Rep 2012;28:1339-45.
9. Yamai H, Sawada N, Yoshida T, Seike J, Takizawa H, Kenzaki K, et al. Triterpenes augment the inhibitory effects of anticancer drugs on the growth of human esophageal carcinoma cells in vitro and suppress experimental metastasis in vivo. Int J Cancer 2009;125:952–60.
10. Vorobyova O, Deryabina O, Malygina D, Plotnikova N, Solovyeva A, Belyaeva K, et al. Betulin-3,28-diphosphate as a component of combination cytostatic drugs for the treatment of Ehrlich ascites carcinoma in vitro and in vivo experiments. Sci Pharm 2018;86:17.
11. Strazhev SV, Berezantsev AY, Karandeeva TV, Drobyazko AA. The use of hydrazine sulfate in the optimization of palliative medical therapy and improvement of quality of life in cancer patients. Oncol Coloproctol 2014;2:13–7.
12. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003;3:330-8.
13. Zheng J. Energy metabolism of cancer: glycolysis versus oxidative phosphorylation (Review). Oncol Lett 2012;4:1151-7.
14. Kislitsyn AN, Trofimov AN, Patlasov VP, Chuprova VA. Pat. 2150473 Russian Federation, C07J53/00. Method of betulinol diacetate preparing [Text]. State Unitary Enterprise Central Research and Design Institute of the Wood Chemical Industry; 2020.
15. Melnikova N, Burlova I, Kiseleva T, Klabukova I, Gulenova M, Kislitsin ?, et al. A practical synthesis of betulonic acid using selective oxidation of betulin on aluminum solid support. Molecules 2012;17:11849-63.
16. Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978;86:271-8.
17. Sirota TV. A new approach to the investigation of adrenaline autooxidation and its application for the determination of superoxide dismutase activity. ?Biochem (Moscow) Suppl Series B: Biomed Chem 1999;45:263-72.
18. Soloveva AG, Zimin YV. A new way to assess the dynamics of blood metabolism in patients with thermal trauma. Mod Technol Med 2012;2:116-7.
19. Waterborg JH, Matthews HR. The Lowry method for protein quantitation. Methods Mol Biol 1994;32:1-4.
20. Begemann H, Rastetter J. Staining methods. In: Begemann H, Rastetter J. editors. Atlas of clinical haematology. Berlin, Heidelberg: Springer; 1972. p. 9-12.
21. Rajeshwar Y, Gupta M, Mazumder UK. Antitumor activity and in vivo antioxidant status of Mucuna pruriens (Fabaceae) seeds against Ehrlich ascites carcinoma in swiss albino mice. Iranian J Pharmacol Ther 2005;4:46-53.
22. Hossain E, Chakroborty S, Milan A, Chattopadhyay P, Mandal SC, Gupta JK. In vitro and in vivo antitumor activity of a methanol extract of Dregea volubilis leaves with its antioxidant effect. Pharm Biol 2012;50:338-43.
23. Gnanaraja R, Veeru P, Mahendra V. Antitumor activity and in vivo antioxidant status of T. Purpurea against dena induced hepatocellular carcinoma in swiss albino mice. Indian J Sci Res 2014;9:22-7.
24. Sivakumar P, Sambath Kumar R, Sivakumar T, Nethaji R, Vijayabaskaran M, Perumal P, et al. Antitumor and antioxidant activities of Triumfetta Rhomboidea against dalton’s ascites lymphoma bearing swiss albino mice. Res J Med Sci 2008;2:203-8.
25. Sun Y, Oberley LW, Elwell JH, Sierra Rivera E. Antioxidant enzyme activities in normal and transformed mice liver cells. Int J Cancer 1989;44:1028-33.
26. Christova T, Gorneva G, Taxirov S, Setchenska M. Effect of 5-fluorouracil and cobalt chloride on antioxidant enzymes and heme oxygenase in the livers of Lewis lung carcinoma-bearing mice. C R Acad Bulg Sci 2003;56:93-8.
27. Selvendiran K, Singh JP, Krishnan KB, Sakthisekaran D. Cytoprotective effect of piperine against benzo[a]pyrene induced lung cancer with reference to lipid peroxidation and antioxidant system in swiss albino mice. Fitoterapia 2003;74:109-15.
28. Gold J. Inhibition of gluconeogenesis at the phosphoenolpyruvate carboxykinase and pyruvate carboxylase reactions, as mean cancer chemotherapy. Oncology 1974;29:74-89.
This work is licensed under a Creative Commons Attribution 4.0 International License.