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Antitumor activity in vitro of glycyrrhetinic acid and its combinations with calcium signaling modulators

https://doi.org/10.29235/1814-6023-2026-23-1-57-67

Abstract

The antitumor activity in vitro of glycyrrhetinic acid and its combinations with modulators of cellular calcium metabolism and inhibitors of calcium-binding proteins was studied. It was shown that glycyrrhetinic acid dose-dependently suppresses the growth of glioma C6 and HeLa. Enhancement of the inhibitory effect can be achieved by combining glycyrrhetinic acid with A23187 (calcium ionophore), chlorpromazine (calmodulin inhibitor), cyclosporine (calcineurin inhibitor), U73122 (phospholipase C inhibitor), ruthenium red (inhibitor of vanilloid channels of transient receptor potential and mitochondrial Ca2+-uniporter), which provides a more pronounced effect than the use of glycyrrhetinic acid and the above compounds separately. Tumor cells of glioma C6 and HeLa were more sensitive to glycyrrhetinnic acid, the studied modulators of cellular calcium metabolism and combinations of glycyrrhetinic acid with these modulators than normal cells of primary rat brain culture.

About the Authors

T. I. Terpinskaya
Institute of Physiology of the National Academy of Sciences of Belarus
Belarus

Tatyana I. Terpinskaya – Ph. D. (Biol.), Associate Professor, Leading Researcher 

28, Akademicheskaya Str., 220072, Minsk



K. V. Markevich
Institute of Physiology of the National Academy of Sciences of Belarus
Belarus

Karina V. MarkevichJunior Researcher, Postgraduate Student 

28, Akademicheskaya Str., 220072, Minsk



E. F. Polukoshko
Institute of Physiology of the National Academy of Sciences of Belarus
Belarus

Elena F. PolukoshkoSenior Researcher 

28, Akademicheskaya Str., 220072, Minsk



References

1. Sharifi-Rad J., Quispe C., Herrera-Bravo J., Belén L. H., Kaur R., Kregiel D. [et al.]. Glycyrrhiza Genus: Enlightening Phytochemical Components for Pharmacological and Health-Promoting Abilities. Oxidative Medicine and Cellular Longevity, 2021, vol. 2021, art. 7571132. https://doi.org/10.1155/2021/7571132

2. Shinu P., Gupta G. L., Sharma M., Khan S., Goyal M., Nair A. B. [et al.]. Pharmacological Features of 18β-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic Potential. Plants, 2023, vol. 12, no. 5, art. 1086. https://doi.org/10.3390/plants12051086

3. Terpinskaya T. I. Antitumor properties of glycyrrhizic and glycyrrhetic acids. Novosti mediko-biologicheskikh nauk = News of biomedical sciences, 2023, vol. 23, no. 3, pp. 235‒252 (in Russian).

4. Jain R., Hussein M. A., Pierce S., Martens C., Shahagadkar P., Munirathinam G. Oncopreventive and oncotherapeutic potential of licorice triterpenoid compound glycyrrhizin and its derivatives: Molecular insights. Pharmacological Research, 2022, vol. 178, art. 106138. https://doi.org/10.1016/j.phrs.2022.106138

5. Zhang Y., Sheng Z., Xiao J., Li Y., Huang J., Jia J., Zeng X., Li L. Advances in the roles of glycyrrhizic acid in cancer therapy. Frontiers in Pharmacology, 2023, vol. 14, art. 1265172. https://doi.org/10.3389/fphar.2023.1265172

6. Dycha N., Michalak-Tomczyk M., Jachuła J., Okoń E., Jarząb A., Tokarczyk J., Koch W., Gaweł-Bęben K., KukulaKoch W., Wawruszak A. Chemopreventive and Anticancer Activity of Selected Triterpenoids in Melanoma. Cancers, 2025, vol. 17, no. 10, art. 1625. https://doi.org/10.3390/cancers17101625

7. Terpinskaya T. I., Yanchenko T. L., Rubinskaya M. A., Polukoshko E. F. Effect of betulinic acid and calcium metabolism modulators on tumor cell growth. Biokhimiya i molekulyarnaya biologiya = Biochemistry and molecular biology, 2024, vol. 3, no. 1, pp. 136‒142 (in Russian).

8. Terpinskaya T. I., Markevich K. V., Rubinskaya M. A., Yanchenko T. L., Polukoshko E. F., Piven’ Yu. A. Effect of TRP channel antagonists and calcium-binding protein inhibitors on the antitumor effect of a betulinic acid derivative in vitro. Novosti mediko-biologicheskikh nauk = News of biomedical sciences, 2024, vol. 24, no. 3, pp. 121‒122 (in Russian).

9. Liu X., Feng C., Yan L., Cao J., Zhu X., Li M., Zhao G. Calcium channels as pharmacological targets for cancer therapy. Clinical and Experimental Medicine, 2025, vol. 25, no. 1, art. 94. https://doi.org/10.1007/s10238-025-01632-z

10. Yang M. H., Jung S. H., Sethi G., Ahn K. S. Pleiotropic Pharmacological Actions of Capsazepine, a Synthetic Analogue of Capsaicin, against Various Cancers and Inflammatory Diseases. Molecules, 2019, vol. 24, no. 5, art. 995. https://doi.org/10.3390/molecules24050995

11. Haustrate A., Cordier C., Shapovalov G., Mihalache A., Desruelles E., Soret B. [et al.]. Trpv6 channel targeting using monoclonal antibody induces prostate cancer cell apoptosis and tumor regression. Cell Death and Disease, 2024, vol. 15, no 6, art. 419. https://doi.org/10.1038/s41419-024-06809-0

12. Lee H., Kim J. W., Lee D.-S., Min S.-H. Combined Poziotinib with Manidipine Treatment Suppresses Ovarian Cancer Stem-Cell Proliferation and Stemness. International Journal of Molecular Sciences, 2020, vol. 21, no. 19, art. 7379. https://doi.org/10.3390/ijms21197379

13. Mukhopadhyay D., Goel H. L., Xiong C., Goel S., Kumar A., Li R., Zhu L. J., Clark J. L., Brehm M. A., Mercurio A. M. The calcium channel TRPC6 promotes chemotherapy-induced persistence by regulating integrin α6 mRNA splicing. Cell Reports, 2023, vol. 42, no. 11, art. 113347. https://doi.org/10.1016/j.celrep.2023.113347

14. Ivanova A. E., Gorbacheva L. R., Strukova S. M., Pinelis V. G., Reiser G. Activated protein C and thrombin participation in the regulation of astrocyte functions Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology, 2014, vol. 8, no. 1, pp. 50‒59. https://doi.org/10.1134/S1990747813050048

15. Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 1983, vol. 65, no. 1–2, pp. 55‒63. https://doi.org/10.1016/0022-1759(83)90303-4

16. Kamgar-Dayhoff P., Brelidze T. I. Multifaceted effect of chlorpromazine in cancer: implications for cancer treatment. Oncotarget, 2021, vol. 12, no. 14, pp. 1406–1426. https://doi.org/10.18632/oncotarget.28010

17. González-Andrade M., Figueroa M., Rodríguez-Sotres R., Mata R., Sosa-Peinado A. An alternative assay to discover potential calmodulin inhibitors using a human fluorophore-labeled CaM protein. Analytical Biochemistry, 2009, vol. 387, no. 1, pp. 64–70. https://doi.org/10.1016/j.ab.2009.01.002

18. Khan S. Z., Longland C. L., Michelangeli F. The effects of phenothiazines and other calmodulin antagonists on the sarcoplasmic and endoplasmic reticulum Ca2+ pumps. Biochemical Pharmacology, 2000, vol. 60, no. 12, pp. 1797‒1806. https://doi.org/10.1016/s0006-2952(00)00505-0

19. Choi S.-Y., Kim Y.-H., Lee Y.-K., Kim K.-T. Chlorpromazine inhibits store-operated calcium entry and subsequent noradrenaline secretion in PC12 cells. British Journal of Pharmacology, 2001, vol. 132, no. 2, pp. 411‒418. https://doi.org/10.1038/sj.bjp.0703840

20. Krutetskaya Z. I., Milenina L. S., Antonov V. G., Nozdrachev A. D. Neuroleptic Chlorpromazine Modulates Ca2+ Responses in Macrophages. Doklady Biochemistry and Biophysics, 2020, vol. 490, no. 1, pp. 25‒28. https://doi.org/10.1134/S160767292001010x

21. Milenina L. S., Krutetskaya Z. I., Antonov V. G., Krutetskaya N. I. Sigma-1 Receptor Ligands Chlorpromazine and Trifluoperazine Attenuate Ca2+ Responses in Rat Peritoneal Macrophages. Cell and Tissue Biology, 2022, vol. 16, no. 3, pp. 233‒244. https://doi.org/10.1134/S1990519x22030075

22. Creamer T. P. Calcineurin. Cell Communication and Signaling, 2020, vol. 18, no 1, art. 137. https://doi.org/10.1186/s12964-020-00636-4

23. Chen L., Song M., Yao C. Calcineurin in development and disease. Genes and Diseases, 2021, vol. 9, no. 4, pp. 915–927. https://doi.org/10.1016/j.gendis.2021.03.002

24. Gao L., Dong J., Zhang N., Le Z., Ren W., Li S., Li F., Song J., Wang Q., Dou Z., Park S. Y., Zhi K. Cyclosporine A Suppresses the Malignant Progression of Oral Squamous Cell Carcinoma in vitro. Anti-Cancer Agents in Medicinal Chemistry, 2019, vol. 19, no. 2, pp. 248–255. https://doi.org/10.2174/1871520618666181029170605

25. Flores C., Fouquet G., Moura I. C., Maciel T. T., Hermine O. Lessons to Learn From Low-Dose Cyclosporin-A: A New Approach for Unexpected Clinical Applications. Frontiers in Immunology, 2019, vol. 10, art. 588. https://doi.org/10.3389/fimmu.2019.00588

26. Siddiqui S. S., Hodeify R., Mathew S., Alsawaf S., Alghfeli A., Matar R. [et al.]. Differential dose-response effect of cyclosporine A in regulating apoptosis and autophagy markers in MCF-7 cells. Inflammopharmacology, 2023, vol. 31, no. 4, pp. 2049–2060. https://doi.org/10.1007/s10787-023-01247-4

27. Yu X., Dai C., Zhao X, Huang Q., He X., Zhang R., Lin Z., Shen Y. Ruthenium red attenuates acute pancreatitis by inhibiting MCU and improving mitochondrial function. Biochemical and Biophysical Research Communications, 2022, vol. 635, pp. 236–243. https://doi.org/10.1016/j.bbrc.2022.10.044

28. Jara-Oseguera A. Ruthenium red: Blocker or antagonist of TRPV channels? Cell Calcium, 2024, vol. 119, art. 102874. https://doi.org/10.1016/j.ceca.2024.102874

29. Pumroy R. A., De Jesús-Pérez J. J., Protopopova A. D., Rocereta J. A., Fluck E. C., Fricke T., Lee B. H., Rohacs T., Leffler A., Moiseenkova-Bell V. Molecular details of ruthenium red pore block in TRPV channels. EMBO Reports, 2024, vol. 25, no. 2, pp. 506–523. https://doi.org/10.1038/s44319-023-00050-0

30. Singh P., Sharma B. Reversal in Cognition Impairments, Cholinergic Dysfunction, and Cerebral Oxidative Stress Through the Modulation of Ryanodine Receptors (RyRs) and Cysteinyl Leukotriene-1 (CysLT1) Receptors. Current Neurovascular Research, 2016, vol. 13, no. 1, pp. 10–21. https://doi.org/10.2174/1567202612666151026105610

31. Saura J. Microglial cells in astroglial cultures: a cautionary note. Journal of Neuroinflammation, 2007, vol. 4, art. 26. https://doi.org/10.1186/1742-2094-4-26


Review

For citations:


Terpinskaya T.I., Markevich K.V., Polukoshko E.F. Antitumor activity in vitro of glycyrrhetinic acid and its combinations with calcium signaling modulators. Proceedings of the National Academy of Sciences of Belarus, Medical series. 2026;23(1):57-67. (In Russ.) https://doi.org/10.29235/1814-6023-2026-23-1-57-67

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ISSN 1814-6023 (Print)
ISSN 2524-2350 (Online)