Non-small cell lung cancer sensitisation to platinum chemotherapy via new thiazole-triazole hybrids acting as dual T-type CCB/MMP-9 inhibitors.
J Enzyme Inhib Med Chem
; 39(1): 2388209, 2024 Dec.
Article
en En
| MEDLINE
| ID: mdl-39140776
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tiazoles
/
Triazoles
/
Ensayos de Selección de Medicamentos Antitumorales
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Carcinoma de Pulmón de Células no Pequeñas
/
Metaloproteinasa 9 de la Matriz
/
Proliferación Celular
/
Relación Dosis-Respuesta a Droga
/
Neoplasias Pulmonares
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
J Enzyme Inhib Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Egipto