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01-08-2019 | Original Article

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

Authors: Deysi Viviana Tenazoa Wong, Helder Veras Ribeiro-Filho, Carlos Wagner Souza Wanderley, Caio Abner Vitorino Gonçalves Leite, Jonilson Berlink Lima, Alexia Nathália Brígido Assef, Aurilene Gomes Cajado, Gabriela Loiola Ponte Batista, Rafael Holanda González, Karla Oliveira Silva, Luis Philipi Carvalho Borges, Nylane Maria Nunes Alencar, Diego Veras Wilke, Thiago Mattar Cunha, Ana Carolina Migliorini Figueira, Fernando Queiroz Cunha, Roberto César Pereira Lima-Júnior

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2019

Abstract

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.

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Title: SN-38, the active metabolite of irinotecan, inhibits the acute inflammatory response by targeting toll-like receptor 4
Authors: Deysi Viviana Tenazoa Wong
Helder Veras Ribeiro-Filho
Carlos Wagner Souza Wanderley
Caio Abner Vitorino Gonçalves Leite
Jonilson Berlink Lima
Alexia Nathália Brígido Assef
Aurilene Gomes Cajado
Gabriela Loiola Ponte Batista
Rafael Holanda González
Karla Oliveira Silva
Luis Philipi Carvalho Borges
Nylane Maria Nunes Alencar
Diego Veras Wilke
Thiago Mattar Cunha
Ana Carolina Migliorini Figueira
Fernando Queiroz Cunha
Roberto César Pereira Lima-Júnior
Publication date: 01-08-2019
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03844-z

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