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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

The small organic molecule C19 binds and strengthens the KRAS4b-PDEδ complex and inhibits growth of colorectal cancer cells in vitro and in vivo

Authors: Pedro Cruz-Nova, Michael Schnoor, José Correa-Basurto, Martiniano Bello, Paola Briseño-Diaz, Arturo Rojo-Domínguez, Carlos M. Ortiz-Mendoza, Jorge Guerrero-Aguirre, Francisco J. García-Vázquez, Rosaura Hernández-Rivas, María del Rocío Thompson-Bonilla, Miguel Vargas

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

Colorectal cancer is the third most common cancer worldwide; and in 40% of all cases, KRAS4b-activating mutations occur. KRAS4b is transported by phosphodiesterase-6δ (PDEδ) to the plasma membrane, where it gets activated. PDEδ downregulation prevents redistribution and activation of KRAS4b. Thus, targeting the KRAS4b-PDEδ complex is a treatment strategy for colorectal cancer.

Methods

Using docking and molecular dynamics simulations coupled to molecular mechanics, the generalized born model and solvent accessibility (MMGBSA) approach to explore protein-ligand stability, we found that the compound ((2S)-N-(2,5-diclorofenil)-2-[(3,4-dimetoxifenil)metilamino]-propanamida), termed C19, bound and stabilized the KRAS4b-PDEδ complex. We investigated whether C19 decreases the viability and proliferation of colorectal cancer cells, in addition to knowing the type of cell death that it causes and if C19 decreases the activation of KRAS4b and their effectors.

Results

C19 showed high cytotoxicity in the colorectal cancer cell lines HCT116 and LoVo, with a stronger effect in KRAS-dependent LoVo cells. Importantly, C19 significantly decreased tumor size in a xenograft mouse model and showed lower side effects than 5-fluorouracil that is currently used as colorectal cancer treatment.

Conclusions

Mechanistically, the cytotoxic effect was due to increased apoptosis of tumor cells and decreased phosphorylation of Erk and Akt. Therefore, our results suggest that C19 may serve as a promising new treatment for colorectal cancer.
Appendix
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Metadata
Title
The small organic molecule C19 binds and strengthens the KRAS4b-PDEδ complex and inhibits growth of colorectal cancer cells in vitro and in vivo
Authors
Pedro Cruz-Nova
Michael Schnoor
José Correa-Basurto
Martiniano Bello
Paola Briseño-Diaz
Arturo Rojo-Domínguez
Carlos M. Ortiz-Mendoza
Jorge Guerrero-Aguirre
Francisco J. García-Vázquez
Rosaura Hernández-Rivas
María del Rocío Thompson-Bonilla
Miguel Vargas
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4968-3

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