RESUMEN
Cisplatin remains the unchallenged standard therapy for NSCLC. However, it is not completely curative due to drug resistance and oxidative stress-induced toxicity. Drug resistance is linked to overexpression of matrix metalloproteinases (MMPs) and aberrant calcium signalling. We report synthesis of novel thiazole-triazole hybrids as MMP-9 inhibitors with T-type calcium channel blocking and antioxidant effects to sensitise NSCLC to cisplatin and ameliorate its toxicity. MTT and whole cell patch clamp assays revealed that 6d has a balanced profile of cytotoxicity (IC50 = 21 ± 1 nM, SI = 12.14) and T-type calcium channel blocking activity (â60% at 10 µM). It exhibited moderate ROS scavenging activity and nanomolar MMP-9 inhibition (IC50 = 90 ± 7 nM) surpassing NNGH with MMP-9 over -2 and MMP-10 over -13 selectivity. Docking and MDs simulated its receptor binding mode. Combination studies confirmed that 6d synergized with cisplatin (CI = 0.69 ± 0.05) lowering its IC50 by 6.89 folds. Overall, the study introduces potential lead adjuvants for NSCLC platinum-based therapy.
Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Neoplasias Pulmonares , Metaloproteinasa 9 de la Matriz , Tiazoles , Triazoles , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Relación Estructura-Actividad , Metaloproteinasa 9 de la Matriz/metabolismo , Tiazoles/química , Tiazoles/farmacología , Tiazoles/síntesis química , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Inhibidores de la Metaloproteinasa de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Cisplatino/farmacología , Cisplatino/química , Canales de Calcio Tipo T/metabolismoRESUMEN
Objective: Hypoxia is one of the principal causes of renal diseases. This study aimed to evaluate the effects of Nigella sativa on dinitrophenol (DNP)-induced hypoxia renal damage in rats. Methods: Forty adult male rats were incorporated in this study. The rats were divided into four groups: control group, N. sativa group, DNP hypoxic group, and DNP + N. sativa group receiving N. sativa (400 mg/kg body weight). Serum and renal tissue erythropoietin (EPO) hormone and hypoxia-inducible factor-2α (HIF-2α) levels were measured. Renal oxidative stress biomarkers, inflammatory biomarkers, renal hemodynamics, and histopathological examination were evaluated. Results: Administration of N. sativa highly significantly normalized serum EPO level, HIF-2α (P < 0.001 for each) in DNP + N. sativa treated rats as compared to DNP hypoxic rats. Furthermore, it highly significantly improved renal oxidative stress evident by decreased renal tissues malondialdehyde and increased superoxide dismutase, total thiol, and catalase activity (P < 0.001 for each). Furthermore, a highly significant decline of renal intercellular adhesion molecule-1, myeloperoxidase, and interleukin-6 was observed in DNP + N. sativa rats (P < 0.001 for each). Improvements in renal hemodynamics and kidney functions were also found after N. sativa administration (with P < 0.001 for all parameters). In addition, N. sativa treatment reduced renal histopathological changes of the DNP + N. sativa group. Our results were statistically analyzed using the Prism software package (GraphPad version 8.0). Conclusion: N. sativa has an alleviating effect on DNP-induced hypoxia renal damage and can restore kidney functions in rats' animal models. These effects were through antioxidant, anti-inflammatory, and hemodynamic mechanisms.