Abstract 1074: The potential of 18β-glycyrrhetinic acid benefit lenvatinib induced cytotoxicity on hepatocellular carcinoma

Abstract

Abstract Hepatocellular carcinoma (HCC) is usually caused by long-term inflammation such as infected by hepatitis B and C viruses. The current standard treatment methods of HCC has included with general surgery, radiation, etc. However, the recurrence rate remain high even after standard treatment, it is necessary to find a better treatment option to control the progression of HCC. Lenvatinib is a multi-endothelial angiogenesis factor inhibitor which is a first-line target drug for the treatment of advanced HCC. Some studies indicated that activation of the PI3K/AKT pathway could lead to the resistance effect of lenvatinib in HCC. 18β-glycyrrhetinic acid (18β-GA) is a hydrolyzed product of glycyrrhizic acid in the intestine. Studies reported that 18β-GA can effectively treat inflammatory diseases and may have antitumor potential. Some studies also indicated that 18β-GA can down-regulate the signaling transduction of PI3K/AKT pathway in various type of cancers. Therefore, in this study, we focused on exploring whether 18β-GA can be used as an adjuvant to downregulate PI3K/AKT signaling and thus enhance the efficacy of lenvatinib on HCC cells and animal model. Here, we used the MTT assay to investigate the cytotoxicity of HCC cells (Huh7 and Hep3B) after various dose of lenvatinib and (or) 18β-GA treatment. We also used combination index (CI) to evaluate the suitable combination condition. In our results, the CI value of lenvatinib 30 μM combined with 18β-GA 100 μM is smaller than 1, which indicated the synergistic effect of combination. We confirmed the superior extrinsic/intrinsic apoptosis induction ability was found in lenvatinib combined with 18β-GA as compared to single treatment. The activation of Fas/FasL pathway, Annexin V, cleaved caspase-3, -8 and -9 were used to confirm the apoptosis induction by lenvatinib combined with 18β-GA. Transwell invasion and wound healing assays results also indicated the invasion/migration suppression ability of lenvatinib combined with 18β-GA on HCC cells. The phosphorylation of AKT were markedly decreased by lenvatinib combined with 18β-GA in HCC cells. Hep3B bearing animal data proved the superior tumor control of lenvatinib combined with 18β-GA. Additionally, the liver function and normal tissue pathology may not affect by combination of lenvatinib and 18β-GA. To conclude, our result demonstrated that 18β-GA may sensitize HCC to lenvatinib via inactivation of PI3K/AKT signaling pathway and induction of extrinsic/intrinsic apoptosis signaling. Citation Format: Yeh Pei-Wen, Yu-Chiang Liu, Yuan Chang, Jiann-Hwa Chen. The potential of 18β-glycyrrhetinic acid benefit lenvatinib induced cytotoxicity on hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1074.