SN-38, the active metabolite of irinotecan, inhibits the acute inflammatory response by targeting toll-like receptor 4

Purpose 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. Methods SN-38, the ac...

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Published in:	Cancer chemotherapy and pharmacology Vol. 84; no. 2; pp. 287 - 298
Main Authors:	Wong, Deysi Viviana Tenazoa, Ribeiro-Filho, Helder Veras, Wanderley, Carlos Wagner Souza, Leite, Caio Abner Vitorino Gonçalves, Lima, Jonilson Berlink, Assef, Alexia Nathália Brígido, Cajado, Aurilene Gomes, Batista, Gabriela Loiola Ponte, González, Rafael Holanda, Silva, Karla Oliveira, Borges, Luis Philipi Carvalho, Alencar, Nylane Maria Nunes, Wilke, Diego Veras, Cunha, Thiago Mattar, Figueira, Ana Carolina Migliorini, Cunha, Fernando Queiroz, Lima-Júnior, Roberto César Pereira
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-08-2019 Springer Nature B.V
Subjects:	Agonists Animals Anticancer properties Binding sites Blocking Cancer Research Cell activation Cell adhesion & migration Computer simulation Cytotoxicity DNA topoisomerase Drug interaction Humans Hydrophobicity Immune system Immunosuppressive agents Inflammation Inflammation - drug therapy Inflammatory response Inhibitors Interleukin 6 Irinotecan Irinotecan - pharmacology Irinotecan - therapeutic use Leukocyte migration Lipopolysaccharides Male Medicine Medicine & Public Health Mice Molecular docking Neutrophils Oncology Original Article Peptidoglycans Pharmacology/Toxicology Proteins TLR2 protein TLR4 protein Toll-Like Receptor 4 - genetics Toll-like receptors Topoisomerase I Inhibitors - pharmacology Topoisomerase I Inhibitors - therapeutic use Topotecan Tumor necrosis factor-α Irinotecan Topotecan SN-38 Inflammation Nuclear factor-κB Toll-like receptor
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Summary:	Purpose 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. Methods 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. Results 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. Conclusions Therefore, SN-38 inhibits acute inflammation by blocking LPS-driven TLR4 signaling. This mechanism seems to be shared by other Top I inhibitors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0344-5704 1432-0843
DOI:	10.1007/s00280-019-03844-z