Abstract A009: Increasing the Sensitivity to sorafenib of Resistant Hepatocellular Carcinoma Cells with Bovine Lactoferrin through Ferroptosis
Authors: Hernandez-Galdamez Hury V , De la Garza Mireya , Rubio Karla , Ramirez-Diaz Ivonne , Guzman-Linares Josue , Acosta Theresa Azcarraga , Barreto Guillermo , stefan günther  , Flores-Tellez Teresita del niño Jesus , Aguilar-Chaparro Mario A , Muriel de la torre Pablo , Reyes-López Magda , Villa-Treviño Saul , Piña-Vazquez Carolina 
Published: November 2024

Abstract
Hepatocellular carcinoma (HCC) remains one of the most lethal cancers worldwide, with a high mortality rate largely due to late-stage diagnosis and the limited efficacy of current therapeutic options. Sorafenib is one of the first-line therapies for advanced HCC. However, its effectiveness is often compromised by the development of drug resistance, significantly limiting its long-term therapeutic potential. This limitation has driven extensive research into alternative therapeutic strategies that can target this resistance, thereby improving the clinical outcomes of patients. Bovine Lf (bLf), which is functionally similar to human Lf (hLf), is safe for human use and has demonstrated anticancer properties, including synergistic effects with chemotherapy. In our study, we explored the role of bovine lactoferrin (bLf) as a potential agent to increase the sensitivity of sorafenib-resistant HCC cells. We developed sorafenib-resistant HCC cell lines through repeated exposure to the drug, with IC50 calculations confirming their increased drug tolerance. These resistant cells were subsequently treated with a combination of sorafenib and bLf. This combination significantly reduced cell viability, with a sorafenib IC50 below the level of the parental sensitive cell line. RNA-seq data revealed significant changes in gene expression profiles, highlighting the differential expression of both mRNAs and long noncoding RNAs (lncRNAs) among resistant, nonresistant, and resistant bLf-treated cells. Further insights were gained through gene set enrichment analysis (GSEA), which identified ferroptosis as a critical pathway significantly enriched in resistant cells treated with bLf and sorafenib vs sorafenib treatment only. Among the differentially expressed lncRNAs, LINC02015 was the most upregulated in resistant cells, and the most downregulated in resistant cells treated with bLf and sorafenib. This lncRNA has emerged as a potentially influencing ferroptosis in other pathologies. Notably, LINC02015 was found to be correlated with HMOX1, a gene with established roles in oxidative stress and iron metabolism. Based on these findings, we conducted a more focused analysis of the ATF3/HMOX1/GPX4 axis, a signaling pathway previously implicated in the regulation of ferroptosis and cellular responses to oxidative stress. Our data suggest that this axis could play a role in modulating lactoferrin-induced ferroptosis in the context of sorafenib resistance. In conclusion, our study provides compelling evidence that bovine lactoferrin (bLf) has the potential to serve as a novel therapeutic agent for overcoming sorafenib resistance in hepatocellular carcinoma by inducing ferroptosis. By potentially targeting the LINC02015/ATF3/HMOX1/GPX4 axis, bLf not only enhances the efficacy of sorafenib but also opens new avenues for the development of combinatory treatment strategies aimed at improving outcomes for HCC patients.
Citation Format: Hury V Hernandez-Galdamez, Mireya De la Garza, Karla Rubio, Ivonne Ramirez-Diaz, Josue Guzman-Linares, Theresa Azcarraga Acosta, Guillermo Barreto, stefan günther, Teresita del niño Jesus Flores-Tellez, Mario A Aguilar-Chaparro, Pablo Muriel de la torre, Magda Reyes-López, Saul Villa-Treviño, Carolina Piña-Vazquez. Increasing the Sensitivity to sorafenib of Resistant Hepatocellular Carcinoma Cells with Bovine Lactoferrin through Ferroptosis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A009.