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 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.
['Wong|Deysi Viviana Tenazoa|DVT|', 'Ribeiro-Filho|Helder Veras|HV|', 'Wanderley|Carlos Wagner Souza|CWS|', 'Leite|Caio Abner Vitorino Gonçalves|CAVG|', 'Lima|Jonilson Berlink|JB|', 'Assef|Alexia Nathália Brígido|ANB|', 'Cajado|Aurilene Gomes|AG|', 'Batista|Gabriela Loiola Ponte|GLP|', 'González|Rafael Holanda|RH|', 'Silva|Karla Oliveira|KO|', 'Borges|Luis Philipi Carvalho|LPC|', 'Alencar|Nylane Maria Nunes|NMN|', 'Wilke|Diego Veras|DV|', 'Cunha|Thiago Mattar|TM|', 'Figueira|Ana Carolina Migliorini|ACM|', 'Cunha|Fernando Queiroz|FQ|', 'Lima-Júnior|Roberto César Pereira|RCP|0000-0002-7033-655X']
D000818:Animals D006801:Humans D007249:Inflammation D000077146:Irinotecan D008297:Male D051379:Mice D051197:Toll-Like Receptor 4 D059004:Topoisomerase I Inhibitors
SN-38 Irinotecan Toll-like receptor Inflammation Nuclear factor-κB Topotecan