Abstract 7197: Elacridar sensitizes liver cancer to the PKC-inhibitor ICA-1S

Abstract

Abstract Liver cancer is a disease in which cancer cells form in the tissues of the liver. Globally, liver cancer is one of the most frequent fatal malignancies; in the United States, liver cancer is the sixth leading cause of cancer death. Generally, there is a poor prognosis for liver cancer. Chemotherapy and immunotherapy are the best available treatment options. This research aims to provide an alternative treatment option with drugs that specifically attack liver cancer cells. Protein Kinase C (PKCs) are signaling molecules that have been reported to be associated with multiple cellular processes and cancer. PKC activity reportedly is elevated in colorectal cancer cells and metastasizes to the liver. 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) is a PKC-ι specific inhibitor we have previously shown to be effective against some cancer cell lines by decreasing cell growth and inducing apoptosis. In this study, we investigated the effectiveness of ICA-1S against liver cancer cell lines; HEPG2 and PLC5/PRF/5. An equal number of HEPG2 and PLC5/PRF/5 cell lines were seeded into 6 well plates, treated with different concentrations (0.1µM, 0.5µM, 1µM, 5µM, and 10µM) of ICA-1s every 24 hours for three days after which the media was discarded, and cells were counted. The percentage inhibition of ICA-1S on HEPG2 and PLC5/PRF/5 cell lines was calculated. To investigate the resistance inflection, the proliferation assay was also conducted with a combination of an efflux pump inhibitor, Elacridar(10µM), and different concentrations (0.1µM to 10µM) of ICA-1S. The expression of PKC-ι was investigated across all treatments. The dose-response result for treatment with ICA-1S for both HEPG2 and PLC5/PRF/5 cell lines showed a resistance inflection point at 0.5µM and 1µM, where the proliferation rate of the cells declined by 50% and 79% for HEPG2, and 41% and 54% for PLC5/PRF/5 respectively; beyond these points, the cell proliferation rate significantly rises. The results of dose-response for treatment with a combination of ICA-1S and Elacridar showed a continuous decline in cell proliferation rate up to 78% and 84% for HEPG2 and PLC5/PRF/5 respectively as the concentrations of ICA-1S increased from 0.1µM to 10µM. The PKC-ι level was downregulated in the combination treatment. We have shown in this study that liver cancer cells exhibit resistance to PKC inhibitor, ICA-1S, at high concentrations. This resistance inflection may be due to several factors including the activation of drug-efflux proteins. Thus, we proved that the introduction of an efflux pump inhibitor, Elacridar, sensitizes the liver cancer cells to ICA-1S, offsets the resistance of the liver cancer cells to ICA-1S at high concentrations, and enables ICA-1S to be effective in downregulating PKC-ι and decreasing cell growth of liver cancer cells. Citation Format: Abigail Oluwafisayo Olatunji, Mahfuza Marzan, Mildred Acevedo-Duncan. Elacridar sensitizes liver cancer to the PKC-inhibitor ICA-1S [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7197.