Antitumor efficacy of 2-(1,1-Dimethyl-1H-Benzo[e]Indol-2-yl)-5,6,7-trichloro-1,3-tropolone on various models of hepatocellular carcinoma.

Abstract

e16265 Background: Hepatocellular carcinoma (HCC) is the most common form of liver cancer, for which multikinase inhibitors are often used in treatment. However, the rapid development of tumor cell resistance to these drugs dictates an urgent need for testing new molecules. Therefore, the aim of this work was to investigate the effect of the pharmacological compound 2-(1,1-dimethyl-1H-benzo[e]indol-2-yl)-5,6,7-trichloro-1,3-tropolone on tumor growth in subcutaneous and orthotopic models of the experimental transplantable Hep G2 HCC in mice. Methods: Hep G2 cells were implanted subcutaneously into donor mice, followed by subsequent passage into recipient mice via subcutaneous and intrahepatic implantation. Micro-CT with contrast enhancement was used to measure intrahepatic tumor nodules. Compounds were administered orally daily after tumor nodules reached 50-60 mm³ for 3 weeks. The concentration of 2-(1,1-dimethyl-1H-benzo[e]indol-2-yl)-5,6,7-trichloro-1,3-tropolone was 60 mg/kg. Sorafenib (20 mg/kg) was used for comparison, and saline solution served as the control. The combination therapy group received both the tropolone and sorafenib at the same concentrations and schedule. Results: At the end of the experiment, the mean volume of subcutaneous and orthotopic tumor nodules was: 804.13 ± 40.56 mm³ and 910.66 ± 51.45 mm³ in the control group; 250.23 ± 18.28 mm³ and 184.26 ± 13.24 mm³ in the combination therapy group; 502.14 ± 31.06 mm³ and 390.14 ± 22.23 mm³ in the tropolone monotherapy group; 295.03 ± 24.99 mm³ and 310.29 ± 14.57 mm³ in the sorafenib monotherapy group, respectively. Tumor Growth Inhibition (TGI) by tropolone monotherapy was more effective in orthotopic models than in subcutaneous ones (57.16% vs. 37.55%), whereas sorafenib did not demonstrate such selectivity (65.93% vs. 63.31%). The highest TGI was observed with combination therapy (68.88% and 79.77% for subcutaneous and orthotopic models, respectively). Although tropolone monotherapy did not demonstrate higher efficacy compared to sorafenib, no body weight loss was observed in animals treated with tropolone, which may indicate its lower toxicity. Conclusions: The antitumor effect of 2-(1,1-dimethyl-1H-benzo[e]indol-2-yl)-5,6,7-trichloro-1,3-tropolone in combination with sorafenib suggests potential synergy or an additive effect between the investigated compounds. The absence of signs of toxic impact from the tropolone could be utilized for developing effective strategies for the compound's application in clinical practice.