Trailblazing real-world-data to confront hepatocellular carcinoma - disinterring repurposable drugs by amalgamating avant-garde stratagems.

Abstract

Drug repurposing is preferred over de-novo drug discovery to unveil the therapeutic applications of existing drug candidates before investing considerable resources in unexplored novel chemical entities. This study demonstrated multifaceted stratagems to reconnoiter promising repurposable candidates against Hepatocellular Carcinoma (HCC) by amalgamating Real-World-Data (RWD) with bioinformatics algorithms corroborated with in-silico and in-vitro studies. At the outset, the RWD from the Food and Drug Administration Adverse Event Reporting System (FAERS) was explored to navigate signals to retrieve repurposable drugs that are inversely associated with HCC via Disproportionality Analysis. Further, transcriptomic analysis was used to capture the potential targets of HCC. Following this, the interactions between repurposable drugs and HCC targets were virtually demonstrated via molecular docking and Molecular Dynamics Simulations (MDS). Furthermore, additional cytotoxicity and gene expression experiments were conducted to corroborate the results. Overall, 64 drugs with Drug Event >5 were shortlisted as prospective repurposable drugs as per the RWD obtained from FAERS. The transcriptomic analysis highlighted significant upregulation of Cyclin A2 (CCNA2) in HCC, which activates Cyclin Dependent Kinase 2 (CDK2). Further, in-silico studies identified Losartan and Allopurinol, with docking scores of -7.11 and -6.219, respectively, as potential repurposable drugs. The selected drugs underwent further scrutiny through in-vitro studies. The treatment of HepG2 cells with Allopurinol resulted in significant downregulation of CCNA2/CDK2 expression with an elevation in reactive oxygen species levels, uncovering Allopurinol's anticancer mechanism through cellular apoptosis. This study suggests the importance of RWD in drug repurposing and the potential of Allopurinol as a repurposable drug against HCC.