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

Autor: Cruz-Nova P; Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Av. I.P.N, 2508, México City, Mexico., Schnoor M; Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Av. I.P.N, 2508, México City, Mexico., Correa-Basurto J; Laboratorio de Modelado Molecular y diseño de fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México City, Mexico., Bello M; Laboratorio de Modelado Molecular y diseño de fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México City, Mexico., Briseño-Diaz P; Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Av. I.P.N, 2508, México City, Mexico., Rojo-Domínguez A; Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana Unidad Cuajimalpa, México City, Mexico., Ortiz-Mendoza CM; Investigación Biomédica y Traslacional, Laboratorio de Medicina Genómica, Hospital 1° de Octubre, ISSSTE, México City, Mexico., Guerrero-Aguirre J; Investigación Biomédica y Traslacional, Laboratorio de Medicina Genómica, Hospital 1° de Octubre, ISSSTE, México City, Mexico., García-Vázquez FJ; Laboratorio de inmunohistoquímica, Instituto Nacional de Pediatría, México City, Mexico., Hernández-Rivas R; Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Av. I.P.N, 2508, México City, Mexico., Thompson-Bonilla MDR; Investigación Biomédica y Traslacional, Laboratorio de Medicina Genómica, Hospital 1° de Octubre, ISSSTE, México City, Mexico., Vargas M; Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Av. I.P.N, 2508, México City, Mexico. mavargas@cinvestav.mx.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2018 Nov 01; Vol. 18 (1), pp. 1056. Date of Electronic Publication: 2018 Nov 01.
DOI: 10.1186/s12885-018-4968-3
Abstrakt: 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.
Databáze: MEDLINE
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