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22.04.2019 | Original Article

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

verfasst von: 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

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2019

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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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Liston A, Masters SL (2017) Homeostasis-altering molecular processes as mechanisms of inflammasome activation. Nat Rev Immunol 17:208–214CrossRef

O’Neill LAJ, Golenbock D, Bowie AG (2013) The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol 13:453–460. https://doi.org/10.1038/nri3446 CrossRef

Rosadini CV, Kagan JC (2017) Early innate immune responses to bacterial LPS. Curr Opin Immunol 44:14–19CrossRefPubMed

Wang JQ, Jeelall YS, Ferguson LL, Horikawa K (2014) Toll-like receptors and cancer: MYD88 mutation and inflammation. Front Immunol 5:1–10

Awasthi S (2014) Toll-like receptor-4 modulation for cancer immunotherapy. Front Immunol 5:1–5. https://doi.org/10.3389/fimmu.2014.00328 CrossRef

Shurin MR (2013) Dual role of immunomodulation by anticancer chemotherapy. Nat Med 19:20–22. https://doi.org/10.1038/nm.3045 CrossRefPubMedPubMedCentral

Ding AH, Porteu F, Sanchez E, Nathan CF (1990) Shared actions of endotoxin and taxol on TNF receptors and TNF release. Science 248:370–372. https://doi.org/10.1126/Science.1970196 CrossRefPubMed

Kawasaki K, Akashi S, Shimazu R et al (2000) Mouse toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J Biol Chem 275:2251–2254. https://doi.org/10.1074/jbc.275.4.2251 CrossRefPubMed

Wanderley CW, Colon DF, Luiz JPM et al (2018) Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1-profile in a TLR4-dependent manner. Cancer Res 78:5891–5900. https://doi.org/10.1158/0008-5472.CAN-17-3480 CrossRefPubMed

10.

Rialdi A, Campisi L, Zhao N et al (2016) Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Science 352:7993. https://doi.org/10.1126/science.aad7993 CrossRefPubMedPubMedCentral

11.

Adams D (2005) The impact of tumor physiology on camptothecin-based drug development. Curr Med Chem Agents 5:1–13. https://doi.org/10.2174/1568011053352596 CrossRef

12.

Danos O, Davies K, Lehn P, Mulligan R (2010) The ARRIVE guidelines, a welcome improvement to standards for reporting animal research. J Gene Med 12:559–560. https://doi.org/10.1002/jgm.1472 CrossRef

13.

Gao H, Zhang X, Chen Y et al (2005) Synthesis and antitumor activity of 7-ethyl-9-alkyl derivatives of camptothecin. Bioorganic Med Chem Lett 15:2003–2006. https://doi.org/10.1016/j.bmcl.2005.02.072 CrossRef

14.

Wang M, Wang L, Guo Y et al (2015) The broad pattern recognition spectrum of the Toll-like receptor in mollusk Zhikong scallop Chlamys farreri. Dev Comp Immunol 52:192–201. https://doi.org/10.1016/j.dci.2015.05.011 CrossRefPubMed

15.

Busuttil V, Bottero V, Frelin C et al (2002) Blocking NF-κB activation in Jurkat leukemic T cells converts the survival agent and tumor promoter PMA into an apoptotic effector. Oncogene 21:3213–3224. https://doi.org/10.1038/sj/onc/1205433 CrossRefPubMed

16.

Skehan P, Storeng R, Scudiero D et al (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82:1107–1112. https://doi.org/10.1093/jnci/82.13.1107 CrossRef

17.

Wittmann M, Penzkofer A (1993) Concentration-dependent absorption and emission behaviour of sulforhodamine B in ethylene glycol. Chem Phys 172:339–348. https://doi.org/10.1016/0301-0104(93)80128-V CrossRef

18.

Boyd MR, Paull KD (1995) Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen. Drug Dev Res 34:91–109. https://doi.org/10.1002/ddr.430340203 CrossRef

19.

Sin Y, Sedgwick A, Chea EP, Willoughby D (1986) Mast cells in newly formed lining tissue during acute inflammation: a six day air pouch model in the mouse. Ann Rheum Dis 45:873–877. https://doi.org/10.1136/ard.45.10.873 CrossRefPubMedPubMedCentral

20.

Leite ACRM, Cunha FQ, Dal-Secco D et al (2009) Effects of nitric oxide on neutrophil influx depends on the tissue: role of leukotriene B4 and adhesion molecules. Br J Pharmacol 156:818–825. https://doi.org/10.1111/j.1476-5381.2008.00094.x CrossRefPubMedPubMedCentral

21.

Dornelas-Filho AF, Pereira VBM et al (2018) Neutrophils contribute to the pathogenesis of hemorrhagic cystitis induced by ifosfamide. Int Immunopharmacol 62:96–108. https://doi.org/10.1016/j.intimp.2018.06.031 CrossRefPubMed

22.

Morris G, Huey R, Lindstrom W et al (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791. https://doi.org/10.1002/jcc.21256.AutoDock4 CrossRefPubMedPubMedCentral

23.

Pettersen EF, Goddard TD, Huang CC et al (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612. https://doi.org/10.1002/jcc.20084 CrossRefPubMed

24.

Andreotti G, Monticelli M, Cubellis MV (2015) Looking for protein stabilizing drugs with thermal shift assay. Drug Test Anal 7:831–834. https://doi.org/10.1002/dta.1798 CrossRefPubMedPubMedCentral

25.

Ribeiro-Filho HV, Videira NB, Bridi AV et al (2018) Screening for PPAR non-agonist ligands followed by characterization of a hit, AM-879, with additional no-adipogenic and cdk5-mediated phosphorylation inhibition properties. Front Endocrinol (Lausanne) 9:1–12. https://doi.org/10.3389/fendo.2018.00011 CrossRef

26.

Videira NB, Batista FAH, Torres Cordeiro A, Figueira ACM (2018) Cellular and biophysical pipeline for the screening of peroxisome proliferator-activated receptor beta/delta agonists: avoiding false positives. PPAR Res 2018:3681590. https://doi.org/10.1155/2018/3681590 CrossRefPubMedPubMedCentral

27.

Holden NS, Squires PE, Kaur M et al (2008) Phorbol ester-stimulated NF-kappaB-dependent transcription: roles for isoforms of novel protein kinase C. Cell Signal 20:1338–1348. https://doi.org/10.1016/j.cellsig.2008.03.001 CrossRefPubMed

28.

Huang Z, Zhao C, Chen Y et al (2014) Recombinant human hyaluronidase PH20 does not stimulate an acute inflammatory response and inhibits lipopolysaccharide-induced neutrophil recruitment in the air pouch model of inflammation. J Immunol 192:5285–5295. https://doi.org/10.4049/jimmunol.1303060 CrossRefPubMed

29.

Mancuso F, Calignano A, Cozzolino A et al (1996) Inhibition of zymosan-induced air-pouch inflammation by rat seminal vesicle protein and by its spermidine derivative. Eur J Pharmacol 312:327–332. https://doi.org/10.1016/0014-2999(96)00394-9 CrossRefPubMed

30.

Aomatsu K, Kato T, Fujita H et al (2008) Toll-like receptor agonists stimulate human neutrophil migration via activation of mitogen-activated protein kinases. Immunology 123:171–180. https://doi.org/10.1111/j.1365-2567.2007.02684.x CrossRefPubMedPubMedCentral

31.

Lima-Júnior RCP, Freitas HC, Wong DVT et al (2014) Targeted inhibition of IL-18 attenuates irinotecan-induced intestinal mucositis in mice. Br J Pharmacol 171:2335–2350. https://doi.org/10.1111/bph.12584 CrossRefPubMedPubMedCentral

32.

Leite CAVG, Alencar VTL, Melo DLR et al (2015) Target inhibition of IL-1 receptor prevents ifosfamide induced hemorrhagic cystitis in mice. J Urol 194:1777–1786. https://doi.org/10.1016/j.juro.2015.07.088 CrossRefPubMed

33.

Wong DVT, Lima-júnior RCP, Carvalho CBM (2015) The Adaptor Protein Myd88 Is a Key Signaling Molecule in the Pathogenesis of Irinotecan-Induced Intestinal Mucositis 10:e0139985. https://doi.org/10.1371/journal.pone.0139985 CrossRef

34.

Pachman DR, Qin R, Seisler D et al (2016) Comparison of oxaliplatin and paclitaxel-induced neuropathy (Alliance A151505). Support Care Cancer 24:5059–5068. https://doi.org/10.1007/s00520-016-3373-1 CrossRefPubMedPubMedCentral

35.

Bao T, Basal C, Seluzicki C et al (2016) Long-term chemotherapy-induced peripheral neuropathy among breast cancer survivors: prevalence, risk factors, and fall risk. Breast Cancer Res Treat 159:327–333. https://doi.org/10.1007/s10549-016-3939-0 CrossRefPubMedPubMedCentral

36.

Byrd-Leifer CA, Block EF, Takeda K et al (2001) The role of MyD88 and TLR4 in the LPS-mimetic activity of Taxol. Eur J Immunol 31:2448–2457. https://doi.org/10.1002/1521-4141(200108)31:8%3c2448:AID-IMMU2448%3e3.0.CO;2-N CrossRefPubMed

37.

Li Y, Zhang H, Zhang H et al (2014) Toll-like receptor 4 signaling contributes to Paclitaxel-induced peripheral neuropathy. J Pain 15:712–725. https://doi.org/10.1016/j.jpain.2014.04.001 CrossRefPubMedPubMedCentral

38.

Underhill DM, Ozinsky A, Hajjar AM et al (1999) The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401:811–815. https://doi.org/10.1038/44605 CrossRefPubMed

39.

Billod JM, Lacetera A, Guzmán-Caldentey J, Martín-Santamaría S (2016) Computational approaches to Toll-like receptor 4 modulation. Molecules. https://doi.org/10.3390/molecules21080994 CrossRefPubMedPubMedCentral

40.

Kuzmich N, Sivak K, Chubarev V, et al (2017) TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis. Vaccines. https://doi.org/10.3390/vaccines5040034 CrossRefPubMedPubMedCentral

41.

Shimazu R, Akashi S, Ogata H et al (1999) MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 189:1777–1782. https://doi.org/10.1084/jem.189.11.1777 CrossRefPubMedPubMedCentral

42.

Chu M, Ding R, Chu Z et al (2014) Role of berberine in anti-bacterial as a high-affinity LPS antagonist binding to TLR4/MD-2 receptor. BMC Complement Altern Med 14:1–9. https://doi.org/10.1186/1472-6882-14-89 CrossRef

43.

Wang Y, Shan X, Chen G et al (2015) MD-2 as the target of a novel small molecule, L6H21, in the attenuation of LPS-induced inflammatory response and sepsis. Br J Pharmacol 172:4391–4405. https://doi.org/10.1111/bph.13221 CrossRefPubMedPubMedCentral

44.

Gradisar H, Keber MM, Pristovsek P, Jerala R (2007) MD-2 as the target of curcumin in the inhibition of response to LPS. J Leukoc Biol 82:968–974. https://doi.org/10.1189/jlb.1206727 CrossRefPubMed

45.

Teghanemt A, Re F, Prohinar P et al (2008) Novel roles in human MD-2 of phenylalanines 121 and 126 and tyrosine 131 in activation of Toll-like receptor 4 by endotoxin. J Biol Chem 283:1257–1266. https://doi.org/10.1074/jbc.M705994200 CrossRefPubMed

46.

Grøftehauge MK, Hajizadeh NR, Swann MJ, Pohl E (2015) Protein-ligand interactions investigated by thermal shift assays (TSA) and dual polarization interferometry (DPI). Acta Crystallogr Sect D Biol Crystallogr 71:36–44. https://doi.org/10.1107/S1399004714016617 CrossRef

47.

Damian L (2013) Isothermal titration calorimetry for studying protein-ligand interactions. Methods Mol Biol 1008:103–118. https://doi.org/10.1007/978-1-62703-398-5_4 CrossRefPubMed

48.

Wardill HR, Gibson RJ, Van Sebille YZA et al (2016) Irinotecan-induced gastrointestinal dysfunction and pain are mediated by common TLR4-dependent mechanisms. Mol Cancer Ther 15:1376–1386. https://doi.org/10.1158/1535-7163.MCT-15-0990 CrossRefPubMed

49.

Riehl T, Cohn S, Tessner T et al (2000) Lipopolysaccharide is radioprotective in the mouse intestine through a prostaglandin-mediated mechanism. Gastroenterology 118:1106–1116. https://doi.org/10.1016/S0016-5085(00)70363-5 CrossRefPubMed

50.

Khan S, Wardill HR, Bowen JM (2018) Role of toll-like receptor 4 (TLR4)-mediated interleukin-6 (IL-6) production in chemotherapy-induced mucositis. Cancer Chemother Pharmacol 82:31–37. https://doi.org/10.1007/s00280-018-3605-9 CrossRefPubMed

Titel: SN-38, the active metabolite of irinotecan, inhibits the acute inflammatory response by targeting toll-like receptor 4
verfasst von: 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
Publikationsdatum: 22.04.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2019
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03844-z

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Springer Medizin

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

Abstract

Purpose

Methods

Results

Conclusions

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Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

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