: 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.
Development and Nanoparticle-Mediated Delivery of Novel MDM2/MDM4 Heterodimer Peptide Inhibitors to Enhance 5-Fluorouracil Nucleolar Stress in Colorectal Cancer Cells / Merlino, Francesco; Pecoraro, Annalisa; Longobardi, Giuseppe; Donati, Greta; Di Leva, Francesco Saverio; Brignola, Chiara; Piccarducci, Rebecca; Daniele, Simona; Martini, Claudia; Marinelli, Luciana; Russo, Giulia; Quaglia, Fabiana; Conte, Claudia; Russo, Annapina; La Pietra, Valeria. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 67:3(2024), pp. 1812-1824. [10.1021/acs.jmedchem.3c01312]
Development and Nanoparticle-Mediated Delivery of Novel MDM2/MDM4 Heterodimer Peptide Inhibitors to Enhance 5-Fluorouracil Nucleolar Stress in Colorectal Cancer Cells
Merlino, Francesco;Pecoraro, Annalisa;Longobardi, Giuseppe;Donati, Greta;Di Leva, Francesco Saverio;Brignola, Chiara;Martini, Claudia;Marinelli, Luciana;Russo, Giulia;Quaglia, Fabiana;Conte, Claudia
;Russo, Annapina
;La Pietra, Valeria
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 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.File | Dimensione | Formato | |
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