Preclinical Assessment of Ezetimibe Combined with Curcumin in Colorectal Cancer Models

The Ezetimibe-curcumin combination (Ezercumin™) is a new anticancer drug developed from the approved drug ezetimibe, combined with curcumin as a protein kinase inhibitor. Ezetimibe is an FDA-approved orally administered drug that blocks intestinal cholesterol uptake, thereby reducing plasma cholesterol levels. Previous studies in our lab showed that ezetimibe binds the MDM2-p53 binding domain and may reactivate p53 in cancers. However, ezetimibe is rapidly metabolized via glucuronidation, limiting its anticancer potential. Curcumin, a known kinase inhibitor, was evaluated for its ability to preserve ezetimibe's active form and enhance its antitumor effect.

We assessed the effects of ezetimibe, curcumin, and their combination on cell viability and cell-cycle progression in CRC cell lines (HCT116, HT-29, and SW620) using xCELLigence technology and flow cytometry. Pharmacokinetics and antitumor efficacy were evaluated in non-tumor-bearing and orthotopic HCT116_Luc xenograft NMRI nude mice in collaboration with Reaction Biology.

Ezetimibe alone induced a marked reduction in the HCT116 cell index, ~70% apoptosis, and a G0/G1 arrest, whereas curcumin alone showed minimal cytotoxicity. In p53-mutant HT-29 and SW620 cells, treatments had no significant effect, reinforcing p53-dependent sensitivity. In vivo early pharmacokinetics showed rapid clearance of ezetimibe and curcumin in co-administration. In the orthotopic CRC model, the combination of ezetimibe and curcumin was associated with modest late reduction in tumour bioluminescence from day 47 onward, indicating tumour size reduction that was not seen with ezetimibe treatment alone during the post-treatment observation period.

The ezetimibe-curcumin combination reduces tumor burden in vivo, demonstrating its therapeutic potential. These preliminary findings suggest the ezetimibe-curcumin combination as a potential anticancer therapeutic and support further studies with optimized dosing and schedules. Currently, an in vivo preclinical study using holofibre technology is underway to determine pharmacokinetics and assess treatment effectiveness across several cancer types, with particular focus on Mdm2-overexpressing cancers.