Abstract B028: Antiproliferative effect of a cathepsin L inhibitor on hepatocellular carcinoma

Abstract

Abstract Liver cancer has emerged as one of the fastest-growing malignancies in the United States, despite an overall decline in cancer incidence and mortality rates. Hepatocellular carcinoma (HCC) exhibits significant gender and race/ethnicity differences in incidence and mortality. The need to address this escalating problem necessitates the development of novel and effective chemotherapeutic agents for HCC. The antiproliferative actions of two cathepsin L inhibitors (compounds 1 and 2) using in vitro and mice HCC xenograft models were investigated in this study. In addition, the ability of the compounds to inhibit CatB and generate ROS in HCC cell lines was investigated. The inhibitors have antiproliferative effects on Hep G2 and Hep 3B cell lines with low micromolar IC 50 values. Compound 1 preferentially inhibits both recombinant and endogenous CatL in a time-dependent manner compared to CatB. The levels of ROS produced when cells were treated with compound 1 were non-significant compared with vehicle-treated controls . Given the superior efficacy of compound 1 over its analog in antiproliferative studies, it was advanced to in vitro ADME studies. The inhibitor has bidirectional cellular permeability and is not a substrate for the P-glycoprotein efflux pump (P-gp). In mice, it produced a significant reduction in the sizes of subcutaneous tumors with no gross toxicity. Transcriptomics analysis using RNA-Seq revealed that the cell migration pathway was enriched in a time and dose-dependent manner. In addition, genes responsible for apoptosis and cell structural organization were overexpressed. Overall, the CatL inhibitors under investigation appear as promising starting points for investigation as potential chemotherapy against HCC. Citation Format: Olamide O. Crown, Ifedayo V. Ogungbe, Felicite K. Noubissi. Antiproliferative effect of a cathepsin L inhibitor on hepatocellular carcinoma [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B028.