SN-38, the active metabolite of irinotecan, inhibits the acute inflammatory response by targeting toll-like receptor 4
| Autor: | Carlos W. S. Wanderley, Thiago M. Cunha, Caio Abner Leite, Jonilson B. Lima, Fernando Q. Cunha, Ana Carolina Migliorini Figueira, Helder Veras Ribeiro-Filho, Diego Veras Wilke, Nylane M.N. Alencar, Rafael Holanda González, Karla Oliveira da Silva, Alexia Nathália Brígido Assef, Deysi Viviana Tenazoa Wong, Luis Philipi Carvalho Borges, Roberto C. P. Lima-Júnior, Gabriela Loiola Ponte Batista, Aurilene Gomes Cajado |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Agonist Cancer Research medicine.drug_class SN-38 Pharmacology RECEPTORES Irinotecan Toxicology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Humans Pharmacology (medical) Receptor Inflammation Toll-like receptor Chemistry Zymosan Toll-Like Receptor 4 030104 developmental biology Oncology Interaction with host 030220 oncology & carcinogenesis TLR4 Topoisomerase I Inhibitors Cell activation |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| Popis: | Anticancer-drug efficacy seems to involve the direct interaction with host immune cells. Although topoisomerase I (Top I) inhibitors have been suggested to block LPS-evoked inflammation, the interaction between these drugs and toll-like receptor 4 (TLR4) is unaddressed. SN-38, the active metabolite of the Top I inhibitor irinotecan, and TLR4 interaction was assessed using the in vitro luciferase nuclear factor-κB reporter assay, neutrophil migration to murine air-pouch, in silico simulation, and the thermal shift assay (TSA). Topotecan was used as a positive anti-inflammatory control. Non-cytotoxic concentrations of SN-38 attenuated LPS (a TLR4 agonist)-driven cell activation without affecting peptidoglycan (a TLR2 agonist)-activating response. Similarly, topotecan also prevented LPS-induced inflammation. Conversely, increasing concentrations of LPS reversed the SN-38 inhibitory effect. In addition, SN-38 abrogated LPS-dependent neutrophil migration and reduced TNF-α, IL-6, and keratinocyte chemoattractant levels in the air-pouch model, but failed to inhibit zymosan (a TLR2 agonist)-induced cell migration. A two-step molecular docking analysis indicated two potential binding sites for the SN-38 in the MD-2/TLR4 complex, the hydrophobic MD-2 pocket (binding energy of − 8.1 kcal/mol) and the rim of the same molecule (− 6.9 kcal/mol). The topotecan also bound to the MD-2 pocket. In addition, not only the lactone forms, but also the carboxylate conformations of both Top I inhibitors interacted with the MD-2 molecule. Furthermore, the TSA suggested the interaction of SN-38 with MD-2. Therefore, SN-38 inhibits acute inflammation by blocking LPS-driven TLR4 signaling. This mechanism seems to be shared by other Top I inhibitors. |
| Databáze: | OpenAIRE |
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