1,2,4-triazole-3-carboxamides induces G2/M cell cycle arrest in ovarian cancer cell lines

Introduction. Ovarian cancer is one of the most common gynecological cancers worldwide, which is difficult to diagnose and treat. the high mortality rate from ovarian cancer makes the development of new therapeutic drugs relevant. Ribavirin (RBV), commonly used antiviral agent, revealed the anticancer potential, however, it led to the development of severe side effects as well. RBV derivatives were previously synthesized and tested as putative anticancer drugs in the models of hematological malignancies. The aim of this study was to estimate the anticancer effects of and RBV derivatives (MGs) in ovarian cancer cells in vitro. Material and Methods. Cytotoxic and cytostatic effects of the MGs on ovarian cancer cells (OVCAR3 and OVCAR4) were assessed using the MTT assay and cell counting with trypan blue staining. distribution of cell cycle phases and induction of apoptosis was evaluated using flow cytometry with propidium iodide and annexin V-FITC staining. Results. 1,2,4-triazole-3-carboxamides inhibited the proliferation and induced cell cycle arrest of ovarian cancer cells in vitro. Conclusion. these results provide the rationale for further studies of 1,2,4-triazole-3-carboxamides as anticancer drugs.

1. Cancer care for the population of Russia in 2022. Ed. by A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova. Moscow, 2023. 252 p. (in Russian).

2. Ozols R.F., Bundy B.N., Greer B.E., Fowler J.M., Clarke-Pearson D., Burger R.A., Mannel R.S., DeGeest K., Hartenbach E.M., Baergen R.; Gynecologic Oncology Group. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003; 21(17): 3194–200. doi: 10.1200/JCO.2003.02.153.

3. Gorodnova T.V., Sokolenko A.P., Kuligina E., Berlev I.V., Imyanitov E.N. Principles of clinical management of ovarian cancer. Chin Clin Oncol. 2018; 7(6): 56. doi: 10.21037/cco.2018.10.06.

4. Galmarini C.M., Mackey J.R., Dumontet C. Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol. 2002; 3(7): 415–24. doi: 10.1016/s1470-2045(02)00788-x.

5. Pfisterer J., Plante M., Vergote I., du Bois A., Hirte H., Lacave A.J., Wagner U., Stähle A., Stuart G., Kimmig R., Olbricht S., Le T., Emerich J., Kuhn W., Bentley J., Jackisch C., Lück H.J., Rochon J., Zimmermann A.H., Eisenhauer E.; AGO-OVAR; NCIC CTG; EORTC GCG. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006; 24(29): 4699–707. doi: 10.1200/JCO.2006.06.0913.

6. Savinkova A.V., Zhidkova E.M., Tilova L.R., Lavrova M.D., Lylova E.S., Kuzin K.A., Portyannikova A.Yu., Maximova V.P., Kholodova A.V., Vlasova O.A., Fetisov T.I., Kirsanov K.I., Belitskiy G.A., Yakubovskaya M.G., Lesovaya E.A. Variants and perspectives of drug repurposing for cancer treatment. Siberian Journal of Oncology. 2018; 17(3): 77–87. (in Russian). doi: 10.21294/1814-4861-2018-17-3-77-87.

7. Huq S., Casaos J., Serra R., Peters M., Xia Y., Ding A.S., Ehresman J., Kedda J.N., Morales M., Gorelick N.L., Zhao T., Ishida W., Perdomo-Pantoja A., Cecia A., Ji C., Suk I., Sidransky D., Brait M., Brem H., Skuli N., Tyler B. Repurposing the FDA-Approved Antiviral Drug Ribavirin as Targeted Therapy for Nasopharyngeal Carcinoma. Mol Cancer Ther. 2020; 19(9): 1797–808. doi: 10.1158/1535-7163.MCT-19-0572.

8. Chen J., Xu X., Chen J. Clinically relevant concentration of antiviral drug ribavirin selectively targets pediatric osteosarcoma and increases chemosensitivity. Biochem Biophys Res Commun. 2018; 506(3): 604–10. doi: 10.1016/j.bbrc.2018.10.124. Erratum in: Biochem Biophys Res Commun. 2023; 686. doi: 10.1016/j.bbrc.2023.09.081.

9. Teng L., Ding D., Chen Y., Dai H., Liu G., Qiao Z., An R. Anti-tumor effect of ribavirin in combination with interferon-α on renal cell carcinoma cell lines in vitro. Cancer Cell Int. 2014; 14: 63. doi: 10.1186/1475-2867-14-63.

10. Pettersson F., Yau C., Dobocan M.C., Culjkovic-Kraljacic B., Retrouvey H., Puckett R., Flores L.M., Krop I.E., Rousseau C., Cocolakis E., Borden K.L., Benz C.C., Miller W.H. Jr. Ribavirin treatment effects on breast cancers overexpressing eIF4E, a biomarker with prognostic specificity for luminal B-type breast cancer. Clin Cancer Res. 2011; 17(9): 2874–84. doi: 10.1158/1078-0432.CCR-10-2334. Erratum in: Clin Cancer Res. 2011; 17(21): 6952. Retrouvay, Hélène [corrected to Retrouvey, Hélène].

11. Casaos J., Huq S., Lott T., Felder R., Choi J., Gorelick N., Peters M., Xia Y., Maxwell R., Zhao T., Ji C., Simon T., Sesen J., Scotland S.J., Kast R.E., Rubens J., Raabe E., Eberhart C.G., Jackson E.M., Brem H., Tyler B., Skuli N. Ribavirin as a potential therapeutic for atypical teratoid/rhabdoid tumors. Oncotarget. 2018; 9(8): 8054–67. doi: 10.18632/oncotarget.23883.

12. Shen X., Zhu Y., Xiao Z., Dai X., Liu D., Li L., Xiao B. Antiviral Drug Ribavirin Targets Thyroid Cancer Cells by Inhibiting the eIF4E-β-Catenin Axis. Am J Med Sci. 2017; 354(2): 182–89. doi: 10.1016/j.amjms.2017.03.025.

13. Ochiai Y., Sano E., Okamoto Y., Yoshimura S., Makita K., Yamamuro S., Ohta T., Ogino A., Tadakuma H., Ueda T., Nakayama T., Hara H., Yoshino A., Katayama Y. Efficacy of ribavirin against malignant glioma cell lines: Follow-up study. Oncol Rep. 2018; 39(2): 537–44. doi: 10.3892/or.2017.6149.

14. Dominguez-Gomez G., Cortez-Pedroza D., Chavez-Blanco A., Taja-Chayeb L., Hidalgo-Miranda A., Cedro-Tanda A., Beltran-Anaya F., Diaz-Chavez J., Schcolnik-Cabrera A., Gonzalez-Fierro A., Dueñas-Gonzalez A. Growth inhibition and transcriptional effects of ribavirin in lymphoma. Oncol Rep. 2019; 42(3): 1248–56. doi: 10.3892/or.2019.7240.

15. Urtishak K.A., Wang L.S., Culjkovic-Kraljacic B., Davenport J.W., Porazzi P., Vincent T.L., Teachey D.T., Tasian S.K., Moore J.S., Seif A.E., Jin S., Barrett J.S., Robinson B.W., Chen I.L., Harvey R.C., Carroll M.P., Carroll A.J., Heerema N.A., Devidas M., Dreyer Z.E., Hilden J.M., Hunger S.P., Willman C.L., Borden K.L.B., Felix C.A. Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia. Oncogene. 2019; 38(13): 2241–62. doi: 10.1038/s41388-018-0567-7.

16. Kökény S., Papp J., Weber G., Vaszkó T., Carmona-Saez P., Oláh E. Ribavirin acts via multiple pathways in inhibition of leukemic cell proliferation. Anticancer Res. 2009; 29(6): 1971–80.

17. Li W., Shen F., Weber G. Ribavirin and quercetin synergistically downregulate signal transduction and are cytotoxic in human ovarian carcinoma cells. Oncol Res. 1999; 11(5): 243–7.

18. Wambecke A., Laurent-Issartel C., Leroy-Dudal J., Giffard F., Cosson F., Lubin-Germain N., Uziel J., Kellouche S., Carreiras F. Evaluation of the potential of a new ribavirin analog impairing the dissemination of ovarian cancer cells. PLoS One. 2019; 14(12). doi: 10.1371/journal.pone.0225860.

19. De la Cruz-Hernandez E., Medina-Franco J.L., Trujillo J., Chavez-Blanco A., Dominguez-Gomez G., Perez-Cardenas E., Gonzalez-Fierro A., Taja-Chayeb L., Dueñas-Gonzalez A. Ribavirin as a tri-targeted antitumor repositioned drug. Oncol Rep. 2015; 33(5): 2384–92. doi: 10.3892/or.2015.3816.

20. Kentsis A., Topisirovic I., Culjkovic B., Shao L., Borden K.L. Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc Natl Acad Sci U S A. 2004; 101(52): 18105–10. doi: 10.1073/pnas.0406927102.

21. Pettersson F., Del Rincon S.V., Miller W.H. Jr. Eukaryotic translation initiation factor 4E as a novel therapeutic target in hematological malignancies and beyond. Expert Opin Ther Targets. 2014; 18(9): 1035–48. doi: 10.1517/14728222.2014.937426.

22. Zheng J., Li X., Zhang C., Zhang Y. eIF4E Overexpression Is Associated with Poor Prognoses of Ovarian Cancer. Anal Cell Pathol (Amst). 2020. doi: 10.1155/2020/8984526.

23. Zhidkova E., Stepanycheva D., Grebenkina L., Mikhina E., Maksimova V., Grigoreva D., Matveev A., Lesovaya E. Synthetic 1,2,4-triazole-3-carboxamides Induce Cell Cycle Arrest and Apoptosis in Leukemia Cells. Curr Pharm Des. 2023; 29(43): 3478–87. doi: 10.2174/0113816128275084231202153602.

24. da Costa A.A.B.A., Chowdhury D., Shapiro G.I., D'Andrea A.D., Konstantinopoulos P.A. Targeting replication stress in cancer therapy. Nat Rev Drug Discov. 2023; 22(1): 38–58. doi: 10.1038/s41573-022-00558-5.

25. Tan H., He L., Cheng Z. Inhibition of eIF4E signaling by ribavirin selectively targets lung cancer and angiogenesis. Biochem Biophys Res Commun. 2020; 529(3): 519–25. doi: 10.1016/j.bbrc.2020.05.127.

26. Lim S., Kaldis P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development. 2013; 140(15): 3079–93. doi: 10.1242/dev.091744.

27. Taylor W.R., DePrimo S.E., Agarwal A., Agarwal M.L., Schönthal A.H., Katula K.S., Stark G.R. Mechanisms of G2 arrest in response to overexpression of p53. Mol Biol Cell. 1999; 10(11): 3607–22. doi: 10.1091/mbc.10.11.3607.