<sup>131</sup>I-C19 Iodide Radioisotope and Synthetic I-C19 Compounds as K-Ras4B–PDE6δ Inhibitors: A Novel Approach against Colorectal Cancer—Biological Characterization, Biokinetics and Dosimetry
Pedro Cruz-Nova,
Blanca Ocampo-García,
Dayan Andrea Carrión-Estrada,
Paola Briseño-Diaz,
Guillermina Ferro-Flores,
Nallely Jiménez-Mancilla,
José Correa-Basurto,
Martiniano Bello,
Libia Vega-Loyo,
María del Rocío Thompson-Bonilla,
Rosaura Hernández-Rivas,
Miguel Vargas
Affiliations
Pedro Cruz-Nova
Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-I.P.N.), Gustavo A. Madero, Mexico City 07360, Mexico
Blanca Ocampo-García
Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico
Dayan Andrea Carrión-Estrada
Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-I.P.N.), Gustavo A. Madero, Mexico City 07360, Mexico
Paola Briseño-Diaz
Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-I.P.N.), Gustavo A. Madero, Mexico City 07360, Mexico
Guillermina Ferro-Flores
Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico
Nallely Jiménez-Mancilla
Departamento de Materiales Radiactivos, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico
José Correa-Basurto
Laboratorio de Modelado Molecular y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Gustavo A. Madero, Mexico City 07360, Mexico
Martiniano Bello
Laboratorio de Modelado Molecular y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Gustavo A. Madero, Mexico City 07360, Mexico
Libia Vega-Loyo
Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-I.P.N.), Gustavo A. Madero, Mexico City 07360, Mexico
María del Rocío Thompson-Bonilla
Laboratorio de Medicina Genómica, Hospital Regional 1 de Octubre, ISSSTE, Gustavo A. Madero, Mexico City 07360, Mexico
Rosaura Hernández-Rivas
Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-I.P.N.), Gustavo A. Madero, Mexico City 07360, Mexico
Miguel Vargas
Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-I.P.N.), Gustavo A. Madero, Mexico City 07360, Mexico
In 40–50% of colorectal cancer (CRC) cases, K-Ras gene mutations occur, which induce the expression of the K-Ras4B oncogenic isoform. K-Ras4B is transported by phosphodiesterase-6δ (PDE6δ) to the plasma membrane, where the K-Ras4B–PDE6δ complex dissociates and K-Ras4B, coupled to the plasma membrane, activates signaling pathways that favor cancer aggressiveness. Thus, the inhibition of the K-Ras4B–PDE6δ dissociation using specific small molecules could be a new strategy for the treatment of patients with CRC. This research aimed to perform a preclinical proof-of-concept and a therapeutic potential evaluation of the synthetic I-C19 and 131I-C19 compounds as inhibitors of the K-Ras4B–PDE6δ dissociation. Molecular docking and molecular dynamics simulations were performed to estimate the binding affinity and the anchorage sites of I-C19 in K-Ras4B–PDE6δ. K-Ras4B signaling pathways were assessed in HCT116, LoVo and SW620 colorectal cancer cells after I-C19 treatment. Two murine colorectal cancer models were used to evaluate the I-C19 therapeutic effect. The in vivo biokinetic profiles of I-C19 and 131I-C19 and the tumor radiation dose were also estimated. The K-Ras4B–PDE6δ stabilizer, 131I-C19, was highly selective and demonstrated a cytotoxic effect ten times greater than unlabeled I-C19. I-C19 prevented K-Ras4B activation and decreased its dependent signaling pathways. The in vivo administration of I-C19 (30 mg/kg) greatly reduced tumor growth in colorectal cancer. The biokinetic profile showed renal and hepatobiliary elimination, and the highest radiation absorbed dose was delivered to the tumor (52 Gy/74 MBq). The data support the idea that 131I-C19 is a novel K-Ras4B/PDE6δ stabilizer with two functionalities: as a K-Ras4B signaling inhibitor and as a compound with radiotherapeutic activity against colorectal tumors.
