Development and Nanoparticle-Mediated Delivery of Novel MDM2/MDM4 Heterodimer Peptide Inhibitors to Enhance 5‑Fluorouracil Nucleolar Stress in Colorectal Cancer Cells

Colorectal
cancer (CRC) often involves wild-type p53 inactivation
by MDM2 and MDM4 overexpression, promoting tumor progression and resistance
to 5-fluoruracil (5-FU). Disrupting the MDM2/4 heterodimer can proficiently
reactivate p53, sensitizing cancer cells to 5-FU. Herein, we developed
16 peptides based on Pep3 (1), the only known peptide
acting through this mechanism. The new peptides, notably 3 and 9, showed lower IC50 values than 1. When incorporated into tumor-targeted biodegradable nanoparticles,
these exhibited cytotoxicity against three different CRC cell lines.
Notably, NPs/9 caused a significant increase in p53 levels
associated with a strong increment of its main downstream target p21
inducing apoptosis. Also, the combined treatment of 9 with 5-FU caused the activation of nucleolar stress and a synergic
apoptotic effect. Hence, the co-delivery of MDM2/4 heterodimer disruptors
with 5-FU through nanoparticles might be a promising strategy to overcome
drug resistance in CRC.