RESUMEN
A group of 2-methyl-4-phenylquinoline-chalcone analogs (2a-2x) was synthesized and investigated for anti-depressant, anti-inflammatory, and analgesic effects as cyclooxygenase-2 inhibitors. Pharmacological experiments identified 24 analogs that exhibited anti-depressant, anti-inflammatory, and analgesic activities. In particular, compounds 2c, 2k, and 2w markedly shortened immobility times and exhibited the most anti-depressant activity. In addition, the mechanisms of action of the analogs 2c, 2k, and 2w were likely related to increased serotonin levels in the central nervous system. Compounds 2c, 2k, and 2w displayed reasonable cyclooxygenase-2 inhibitory effects (IC50 values from 0.21 to 0.29 µmol/L) similar to celecoxib (IC50: 0.19 µmol/L) in vitro. A molecular docking study of compound 2k also was conducted.
Asunto(s)
Analgésicos/química , Antiinflamatorios/química , Antidepresivos/química , Chalcona/química , Inhibidores de la Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Analgésicos/metabolismo , Antiinflamatorios/metabolismo , Antidepresivos/metabolismo , Sitios de Unión , Celecoxib/química , Chalcona/metabolismo , Ciclooxigenasa 1/química , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/metabolismo , Diseño de Fármacos , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
[This corrects the article DOI: 10.1155/2020/5135893.].
RESUMEN
OBJECTIVE: The mechanism of enhanced radiosensitivity induced by mitochondrial uncoupling protein UCP2 was investigated in HeLa cells to provide a theoretical basis as a novel target for cervical cancer treatment. METHODS: HeLa cells were irradiated with 4 Gy X-radiation at 1.0 Gy/min. The expression of UCP2 mRNA and protein was assayed by real-time quantitative polymerase chain reaction and western blotting. UCP2 siRNA and negative control siRNA fragments were constructed and transfected into HeLa cells 24 h after irradiation. The effect of UCP2 silencing and irradiation on HeLa cells was determined by colony formation, CCK-8 cell viability, γH2AX immunofluorescence assay of DNA damage, Annexin V-FITC/PI apoptosis assay, and propidium iodide cell cycle assay. The effects on mitochondrial structure and function were investigated with fluorescent probes including dichlorodihydrofluorescein diacetate (DCFH-DA) assay of reactive oxygen species (ROS), rhodamine 123, and MitoTracker Green assay of mitochondrial structure and function. RESULTS: Irradiation upregulated UCP2 expression, and UCP2 knockdown decreased the survival of irradiated HeLa cells. UCP2 silencing sensitized HeLa cells to irradiation-induced DNA damage and led to increased apoptosis, cell cycle arrest in G2/M, and increased mitochondrial ROS. Increased radiosensitivity was associated with an activation of P53, decreased Bcl-2, Bcl-xl, cyclin B, CDC2, Ku70, and Rad51 expression, and increased Apaf-1, cytochrome c, caspase-3, and caspase-9 expression. CONCLUSIONS: UCP2 inhibition augmented the radiosensitivity of cervical cancer cells, and it may be a potential target of radiotherapy of advanced cervical cancer.