Abstract
Ezetimibe is used to treat cardiovascular disease as it blocks the sterol transporter Niemann-Pick C1-Like 1 (NPC1CL1) protein. However, recent evidence indicates that ezetimibe inhibits several cancers, indirectly by reducing circulating cholesterol or via specific signalling pathways. Our in-silico studies indicate that ezetimibe binds to the Tp53 binding domain in Mdm2, forming a more thermodynamically stable complex than nutlin3a. Moreover, we show that Tp53 functions in complex with the Retinoblastoma Binding Protein 6 (RBBP6), another negative regulator of p53, and Mdm2. RBBP6 is dysregulated in many cancers, and various studies and may be a prognostic biomarker for certain cancers. We show that ezetimibe inhibits the growth of several cancer cell lines at concentrations that are not toxic to a normal cell line. Thus ezetimibe is probably active against cancers that overexpress Mdm2. Moreover, inhibitors of RBBP6 may be combined with ezetimibe for effective anticancer activity. Due to poor oral bioavailability ezetimibe must be administered parenterally for cancer treatment.