Discovery of oral chemotherapeutic reversal agents for treating multidrug resistance cancer.
Eur J Pharmacol
; 977: 176682, 2024 Aug 15.
Article
en En
| MEDLINE
| ID: mdl-38823759
ABSTRACT
The major limitation of cancer treatment is multidrug resistance (MDR), which leads to the inactivation of chemotherapeutic drugs and greater than 90% mortality. To solve this ordeal, we applied ligand-based drug design and bioiosteric replacement strategy from an indazole to a pyrazole ring to discover compounds 27 and 43 with good potential for reversing drug resistance in combination with paclitaxel, and their reversal fold values were 53.2 and 51.0 at 5 µM, respectively, against an MDR cancer cell line (KBvin). Based on the PK profile results, we selected compound 43 with a longer half-life for mechanistic and animal experiments. Combination treatment with compound 43 and paclitaxel-induced apoptosis and enhanced subG1 by decreasing mitochondrial membrane potential in KBvin cells. In addition, 43 also inhibited P-gp function by interfering with ATPase activity. Meanwhile, cotreatment with compound 43 and paclitaxel significantly suppressed tumor growth (TGI = 55.5%) at a dose of 200 mg/kg (PO) in a xenograft model and showed no obvious liver or kidney toxicity by H&E staining. Overall, compound 43 may serve as a safe and effective oral resistance reversal chemotherapeutic agent.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Paclitaxel
/
Apoptosis
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Resistencia a Múltiples Medicamentos
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Resistencia a Antineoplásicos
/
Antineoplásicos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Eur J Pharmacol
Año:
2024
Tipo del documento:
Article
País de afiliación:
Taiwán