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Development and Nanoparticle-Mediated Delivery of Novel MDM2/MDM4 Heterodimer Peptide Inhibitors to Enhance 5-Fluorouracil Nucleolar Stress in Colorectal Cancer Cells.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Feb 08; Vol. 67 (3), pp. 1812-1824. Date of Electronic Publication: 2024 Jan 29. - Publication Year :
- 2024
-
Abstract
- 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 IC <subscript>50</subscript> 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.
- Subjects :
- Humans
Fluorouracil pharmacology
Tumor Suppressor Protein p53 metabolism
Apoptosis
Peptides pharmacology
Cell Line, Tumor
Proto-Oncogene Proteins c-mdm2 metabolism
Proto-Oncogene Proteins metabolism
Cell Cycle Proteins metabolism
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Colorectal Neoplasms drug therapy
Nanoparticles
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38285632
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.3c01312