التفاصيل البيبلوغرافية
| العنوان: |
131 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. |
| المؤلفون: |
Cruz-Nova, Pedro, Ocampo-García, Blanca, Carrión-Estrada, Dayan Andrea, Briseño-Diaz, Paola, Ferro-Flores, Guillermina, Jiménez-Mancilla, Nallely, Correa-Basurto, José, Bello, Martiniano, Vega-Loyo, Libia, Thompson-Bonilla, María del Rocío, Hernández-Rivas, Rosaura, Vargas, Miguel |
| المصدر: |
Molecules; Sep2022, Vol. 27 Issue 17, p5446, 22p |
| مصطلحات موضوعية: |
COLORECTAL cancer, MOLECULAR dynamics, RADIATION dosimetry, RAS proteins, RADIOISOTOPES, DOSE-response relationship (Radiation) |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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