A new indolo[2,3-a]carbazole N-glycoside derivative LCS-1269 with antitumor activity on transplantable mice tumors

Background. The study of new representatives of indolo[2,3-a]carbazole N-glycosides with a biological activity broad spectrum remains a relevant direction in the highly effective antitumor drugs creation.

Aim. To evaluate the efficacy of the lyophilized dosage form of a new derivative of indolocarbazole N-glycoside 6-picolinamido-12-(β-D-xylopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (LCS-1269-lyo) on transplantable mice colon adenocarcinoma (CAC) and on SW620 human colon cancer xenografts.

Materials and methods. In studies on female Balb / c mice with subcutaneously (s.c.) transplanted CAC, a single intravenous (i.v.) administration of LCS-1269-lyo was used at doses of 80, 90, 100, 120 mg / kg and five-time administrataion daily at doses of 80 and 90 mg / kg. The LCS-1269-lyo study on SW620 effectiveness was carried out at doses of 60 and 90 mg / kg with five-time daily intraperitoneal (i.p.) administration to male Balb / c nude mice with subcutaneously transplanted SW620 xenografts. The antitumor effect was assessed by tumor growth inhibition and an increase in the lifespan of animals receiving LCS-1269-lyo, compared to the controls.

Results. A dose-dependent reliable antitumor effect of LCS-1269-lyo was observed on CAС after a single exposure at doses of 80, 90, 100 and 120 mg / kg compared to the control group of mice. LCS-1269-lyo, when administered intravenously five times at doses of 80 and 90 mg / kg (total doses of 400 and 450 mg / kg), significantly inhibited CAC growth by 89–88 and 86–84 % (p <0,05) over 30 days of observation and increased the life span of Balb / c mice by 36 and 54 %, respectively. The LCS-1269-lyo effectiveness in a total dose of 450 mg / kg on CAC has been confirmed by the activity of LCS-1269-lyo on SW620 xenografts in Balb / c nude mice with tumor growth inhibition 72,9–71,0 % (p <0,05) during 8 days of observation.

Conclusion. The results of the antitumor activity evaluation of LCS-1269 in a lyophilized dosage form on the model of CAC mice transplantable colon adenocarcinoma and on human colon cancer SW620 subcutaneous xenografts allow to continue preclinical studies of the drug.

1. Kozin D.A., Shprakh Z.S., Reshetnyak V.Yu. et al. Indolo[2,3-a] carbazole derivatives with antitumor activity and instrumental methods for their investigation. Razrabotka y registratsiya lekarstvenykh sredstv = Drug Development & Registration. 2020;9(4):15–20. (In Russ.). DOI: 10.33380/2305-2066-2020-9-4-128-135

2. Kolpaksidi A.P., Dmitrieva M.V., Yarosh I.V., Krasnyuk I.I. Antitumor drugs based on indolocarbazol derivatives. Farmatsiya y farmakologiya = Pharmacy & Pharmacology 2021;9(4):252–65. (In Russ.). DOI: 10.19163/2307-9266-2021-9-4-252-265

3. Zenkov R.G., Ektova L.V., Vlasova O.А. et al. Indolo[2,3-a] carbazoles: diversity, biological properties, application in antitumor therapy. Chem Heterocycl Compd (N Y) 2020;56(6):644–58. DOI: 10.1007/s10593-020-02714-4

4. Stone R.M., Manley P.W., Larson R.A., Capdeville R. Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv 2018;2(4):444–53. DOI: 10.1182/bloodadvances.2017011080

5. He Y., Li J., Ding N. et al. Combination of Enzastaurin and Ibrutinib synergistically induces anti-tumor effects in diffuse large B cell lymphoma. J Exp Clin Cancer Res 2019;38(1):86. DOI: 10.1186/s13046-019-1076-4

6. Yuan Y., Yangmei Z., Rongrong S. et al. Sotrastaurin attenuates the stemness of gastric cancer cells by targeting PKCδ. Biomed Pharmacother 2019;117:109165. DOI: 10.1016/j.biopha.2019.109165

7. Mascarenhas J., Baker M.R., Kessler C. et al. Phase II trial of Lestaurtinib, a JAK2 inhibitor, in patients with myelofibrosis. Leuk Lymphoma 2019;60(5):1343–5. DOI: 10428194.2018.1532509

8. National Center for Biotechnology Information. PubChem Compound Summary for CID 9808998, Edotecarin. URL: https://pubchem.ncbi.nlm.nih.gov/compound/Edotecarin.

9. National Center for Biotechnology Information. PubChem Compound Summary for CID 101524, Becatecarin. URL: https://pubchem.ncbi.nlm.nih.gov/compound/Becatecarin.

10. Mull B.B., Livingston J.A., Patel N. et al. Specific, reversible G1 arrest by UCN-01 in vivo provides cytostatic protection of normal cells against cytotoxic chemotherapy in breast cancer. Br J Cancer 2020;122(6):812–22. DOI: 10.1038/s41416-019-0707-z

11. Odia Y., Iwamoto F.M., Moustakas A. et al. A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas. J Neurooncol 2016;127(1):127–35. DOI: 10.1007/s11060-015-2020-x

12. Ektova L.V., Eremina V.A., Tikhonova N.I. et al. Synthesis and cytotoxic activity of indolo[2,3-a]pyrrolo[3,4-c]carbazole5,7-dione n-glycosides substituted on the maleimide nitrogen atom. Khimiko-farmatsevticheskiy zhurnal = Pharmaceutical Chemistry Journal 2020;54(5):455–8. (In Russ.). DOI: 10.30906/0023-1134-2020-54-5-26-29

13. Nikolaeva L.L., Lantsova A.V., Sanarova E.V. et al. Development of the composition and technology for obtaining a model of an injection form of an indolocarbazole derivative. Khimikofarmatsevticheskiy zhurnal = Pharmaceutical Chemistry Journal 2023;57(6):42–6. (In Russ.). DOI: 10.30906/0023-1134-2023-57-6-42-46

14. Tchurikov N.A., Vartanian A.A., Klushevskaya E.S. et al. Bipolar action of inhibitor of vasculogenic mimicry on gene expression in melanoma cells. Mol Biol (Mosk) 2024;58(2):289–99. DOI: 10.1134/S0026893324020055

15. Kalitin N.N., Ektova L.V., Kostritsa N.S. et al. A novel glycosylated indolocarbazole derivative LCS 1269 effectively inhibits growth of human cancer cells in vitro and in vivo through driving of both apoptosis and senescence by inducing of DNA damage and modulating of AKT/mTOR/S6K and ERK pathways. Chem Biol Interact 2022;364:110056. DOI: 10.1016/j.cbi.2022.110056

16. Zenkov R.G., Vlasova O.A., Maksimova V.P. et al. Molecular mechanisms of anticancer activity of N-Glycosides of indolocarbazoles LCS-1208 and LCS-1269. Molecules 2021;26(23):7329. DOI: 10.3390/molecules26237329

17. Golubeva I.S., Yavorskaya N.P., Ektova L.V. et al. Antitumor activity of some derivatives of indolo[2,3-a]carbazoles N-glycosides with xylose carbohydrate residue. Rossijskij bioterapevticeskij zurnal = Russian Journal of Biotherapy 2020;19(4):86–93. (In Russ.). DOI: 10.17650/1726-9784-2020-19-4-86-93

18. Treshchalina E.M., Smirnova G.B., Andronova N.V. Collection of animal tumor strains for experimental chemotherapy of malignant tumors. Moscow: Prakticheskaya meditsna, 2022. 96 p. (In Russ.).

19. Treschalina E.M., Zhukova O.S., Gerasimova G.K. et al. Methodical recommendations for the preclinical study of the antitumor activity of drugs. In: Guidance on preclinical studies of drugs. Moscow: Grif i K., 2012. Part 1. Р. 642–657. (In Russ.).

20. Treshalina H.M. Immunodeficient mice Balb/c nude and modeling of various types of tumor growth for preclinical studies. Rossijskij bioterapevticeskij zurnal = Russian Journal of Biotherapy 2017;16(3):6–13. (In Russ.). DOI: 10.17650/1726-9784-2017-16-3-6-13]

21. Kiseleva M.P., Borisova L.M., Smirnova G.B. et al. Antiproliferative activity of a new derivative from the class of N-glycoside of indolo[2,3-a]pyrrolo[3,4-c]carbazoles. Research Results in Pharmacology 2022;8(2):49–57. DOI: 10.3897/rrpharmacology.8.79424

22. Ciomi M., Crocе V., Ciavolella A. et al. Antitumor efficacy of edotecarin as a single agent and in combination with chemotherapy agents in a xenograft model. Clin Cancer Res 2006;12(9):2856–61. DOI: 10.1158/1078-0432.CCR-05-1859

23. Jones-Bolin S., Zhao H., Hunter K. et al. The effects of the oral, pan-VEGF-R kinase inhibitor CEP-7055 and chemotherapy in orthotopic models of glioblastoma and colon carcinoma in mice. Mol Cancer Ther 2006;5(7):1744–53. DOI: 10.1158/1535-7163.MCT-05-0327