Antitumor activity of tropolone JO-122(2) in subcutaneous CDX models of cancer

Purpose of the study. The present study investigates the antitumour effect of tropolone 2-(1,1‑dimethyl‑1H-benzo[e]indolin‑2‑yl)-5,6,7‑trichloro‑1,3‑tropolone (JO‑122(2)) in monotherapy and in combination with fluorouracil in subcutaneous CDX models of gastric cancer.
Materials and methods. The experimental work was conducted on female BALB/c Nude mice (n = 32), with ages ranging from 6 to 8 weeks. The CDX models were created by subcutaneous administration of a tumor culture of human gastric adenocarcinoma (AGS) in a dose of 5 × 106 cells per mouse. After the tumors reaching a volume of 70–100 mm³, the animals were divided into four groups of eight individuals each, with the objective of ensuring minimal variation in the mean tumor node volume between groups. The efficacy of the therapeutic intervention was evaluated by measuring the inhibition of tumor growth (TGI %). The statistical data processing was performed using the Microsoft Excel 2013 and STATISTICA 12 software packages. The Mann–Whitney U test was utilized to evaluate the disparities between the experimental and control groups. Differences were considered statistically significant at p < 0.05.
Results. Consequently, subcutaneous CDX models of gastric adenocarcinoma were obtained. The study demonstrated that the administration of JO‑122(2) as a monotherapy did not result in a statistically significant impact on the growth of tumor nodes. The most significant antitumor activity was observed in the group administered combination therapy (JO‑122(2) + 5‑fluorouracil). The mean value of tumor node volumes at the conclusion of the experiment (on day 29 after the commencement of treatment) in this group was 513.98 ± 56.50 mm³, whereas in the control group it was 915.08 ± 49.93 mm³. A comparison of tumor growth rates between the groups receiving 5‑fluorouracil monotherapy and combination therapy revealed statistically significant differences as early as the 22nd day of the experiment. Furthermore, the highest TPO value was observed in the group administered the combination of drugs, at 43.83 %.
Conclusion. The results demonstrated a more effective antitumor effect on gastric adenocarcinoma models when tropolone was used in combination with a cytostatic. This finding suggests the potential for further investigation into the properties of this compound and the possibility of extending its study.

1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229–263. https://doi.org/10.3322/caac.21834

2. Inoue M. Epidemiology of gastric cancer-changing trends and global disparities. Cancers (Basel). 2024 Aug 24;16(17):2948. https://doi.org/10.3390/cancers16172948

3. Malignant neoplasms in Russia in 2020 (morbidity and mortality). Edited by Kaprin AD, Starinsky VV, Shakhzadova AO. Мoscow: P. Hertsen Moscow Oncology Research Institute – Branch of the National Medical Radiology Research Centre of the Ministry of Health of the Russian Federation; 2024, 276 p. (In Russ.). Available at: https://oncology-association.ru/wp-content/uploads/2024/08/zis-2023-elektronnaya-versiya.pdf. Accessed: 08.07.2025.

4. Balsa LM, Ruiz MC, Santa Maria de la Parra L, Baran EJ, León IE. Anticancer and antimetastatic activity of copper(II)-tropolone complex against human breast cancer cells, breast multicellular spheroids and mammospheres. J Inorg Biochem. 2020 Mar;204:110975. https://doi.org/10.1016/j.jinorgbio.2019.110975

5. Gusakov EA, Topchu IA, Mazitova AM, Dorogan IV, Bulatov ER, Serebriiskii IG, et al. Design, synthesis and biological evaluation of 2-quinolyl-1,3-tropolone derivatives as new anti-cancer agents. RSC Adv. 2021;11(8):4555–4571. https://doi.org/10.1039/d0ra10610k

6. Wu PS, Weng JR, Chiu SH, Wu LH, Chen PH, Wang YX, et al. Hinokitiol reduces tumor metastasis by regulating epithelial cell adhesion molecule via protein kinase-B/mammalian target of rapamycin signaling pathway. Am J Cancer Res. 2025 Jan 15;15(1):59–68. https://10.62347/UZFZ9554

7. Khodakova DV, Vlasov SN, Filippova SYu, Goncharova AS, Shulga AA, Golovinov IV, et al. Study of the cytotoxic effect of 2-(1,1-dimethyl-1h-benzo[e]indolin2-yl)-5,6,7-trichloro-1,3-tropolone on the tumor culture of human gastric adenocarcinoma. Modern Problems of Science and Education. 2024;(3). (In Russ.). https://doi.org/10.17513/spno.33440

8. Minkin VI, Kit OI, Saiapin IA, Maksimov AYu, Goncharova AS, Gusakov EA, et al.; inventor; Southern Federal University, National Medical Research Centre for Oncology, assignee. 2-(1,1-dimethyl-1h-benzo[e]indolin-2-yl)-5,6,7-trichloro-1,3-tropolone, which has cytotoxic activity against a431 skin cancer and h1299 lung cancer cell cultures. Russian Federation Patent RU 2810581 C1. 8 Nov 2023. (In Russ.)

9. Chen HY, Cheng WP, Chiang YF, Hong YH, Ali M, Huang TC, et al. Hinokitiol Exhibits Antitumor Properties through Induction of ROS-Mediated Apoptosis and p53-Driven Cell-Cycle Arrest in Endometrial Cancer Cell Lines (Ishikawa, HEC-1A, KLE). Int J Mol Sci. 2021 Jul 31;22(15):8268. https://doi.org/10.3390/ijms22158268

10. Ni YJ, Huang ZN, Li HY, Lee CC, Tyan YC, Yang MH, et al. Hinokitiol impedes tumor drug resistance by suppressing protein kinase B/mammalian targets of rapamycin axis. J Cancer. 2022 Mar 14;13(6):1725–1733. https://10.7150/jca.69449

11. Kamlyk DV, Khodakova DV, Kolesnikov VE, Snezhko AV, Kolesnikov EN, Gurova SV, et al. Evaluation of the antitumor efficacy of 2-(1,1-dimethyl-1h-benzo[e]indolin-2-yl)-5,6,7-trichloro-1,3-tropolone in vivo. Modern Problems of Science and Education. 2025;3. (In Russ.). https://doi.org/10.17513/spno.34062