Targeting Toll like Receptors in Cancer: Role of TLR Natural and Synthetic Modulators

Arunaksharan       Narayanankutty; Aswathi       Sasidharan; Joice    T.    Job
Abstract

Background: Toll like receptors (TLRs) are a group of transmembrane receptors belonging to the broad class pattern recognition receptors (PRR), involved in recognition of Pathogen Associated Molecular Patterns (PAMPs) thereby inducing an immune response. Apart from these exogenous PAMPs, numerous endogenous PAMPs are also ligands for various TLRs thereby activating the TLR dependent immune response, subsequently leading to the onset of an inflammatory response. Prolonged activation of TLR by these endogenous PAMPs leads to chronic inflammatory insults to the body and which in turn alters the proliferative patterns of the cells, which ultimately leads to the development of cancer.
Objectives: The present review aims to provide a detailed outline of the differential roles of various TLRs in cancer and the possible use of them as a therapeutic target.
Methods: Data were collected from PubMed/Sciencedirect/Web of Science database and sorted; the latest literature on TLRs was incorporated in the review.
Results: Among the different TLRs, few are reported to be anti-neoplastic, which controls the cell growth and multiplication in response to the endogenous signals. On the contrary, numerous studies have reported the procarcinogenic potentials of TLRs. Hence, TLRs have emerged as a potential target for the prevention and treatment of various types of cancers. Several molecules, such as monoclonal antibodies, small molecule inhibitors and natural products have shown promising anticancer potential by effectively modulating the TLR signalling.
Conclusion: Toll-like receptors play vital roles in the process of carcinogenesis, hence TLR targeting is a promising approach for cancer prevention.
Keywords: Toll like receptor, cancer, TLR modulators, metastasis, natural products, carcinogenesis.
[1] 
Owen JA, Punt J, Stranford SA. Kuby immunology. New York: WH Freeman 2013.
[2] 
Lemaitre B, Nicolas E, Michaut L, Reichhart J-M, Hoffmann JA. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell  1996; 86(6): 973-83.
[http://dx.doi.org/10.1016/S0092-8674(00)80172-5] [PMID:  8808632] 
[3] 
Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the drosophila toll protein signals activation of adaptive immunity. Nature  1997; 388(6640): 394-7.
[http://dx.doi.org/10.1038/41131] [PMID:  9237759] 
[4] 
Akira S. Toll receptor families: structure and function. Semin Immunol  2004; 16(1): 1-2.
[http://dx.doi.org/10.1016/j.smim.2003.10.001] [PMID:  14751756] 
[5] 
Wu L, Anderson K, Eds. Related signaling networks in Drosophila that control dorsoventral patterning in the embryo and the immune response Cold Spring Harbor symposia on quantitative biology. Cold Spring Harbor Laboratory Press 1997.
[6] 
Bischoff V, Vignal C, Boneca IG, Michel T, Hoffmann JA, Royet J. Function of the drosophila pattern-recognition receptor PGRP-SD in the detection of Gram-positive bacteria. Nat Immunol  2004; 5(11): 1175-80.
[http://dx.doi.org/10.1038/ni1123] [PMID:  15448690] 
[7] 
Levashina EA, Langley E, Green C, et al. Constitutive activation of toll-mediated antifungal defense in serpin-deficient Drosophila. Science  1999; 285(5435): 1917-9.
[http://dx.doi.org/10.1126/science.285.5435.1917] [PMID:  10489372] 
[8] 
Ligoxygakis P, Pelte N, Hoffmann JA, Reichhart J-M. Activation of Drosophila Toll during fungal infection by a blood serine protease. Science  2002; 297(5578): 114-6.
[http://dx.doi.org/10.1126/science.1072391] [PMID:  12098703] 
[9] 
Michel T, Reichhart J-M, Hoffmann JA, Royet J. Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein. Nature  2001; 414(6865): 756-9.
[http://dx.doi.org/10.1038/414756a] [PMID:  11742401] 
[10] 
Brennan CA, Anderson KV. Drosophila: the genetics of innate immune recognition and response. Annu Rev Immunol  2004; 22: 457-83.
[http://dx.doi.org/10.1146/annurev.immunol.22.012703.104626] [PMID:  15032585] 
[11] 
Hultmark D. Drosophila immunity: paths and patterns. Curr Opin Immunol  2003; 15(1): 12-9.
[http://dx.doi.org/10.1016/S0952-7915(02)00005-5] [PMID:  12495727] 
[12] 
Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev  2009; 22(2): 240-73.
[http://dx.doi.org/10.1128/CMR.00046-08] [PMID:  19366914] 
[13] 
Jang J-H, Shin HW, Lee JM, Lee H-W, Kim E-C, Park SH. An Overview of Pathogen Recognition Receptors for Innate Immunity in Dental Pulp. Mediators of inflammation 2015 2015. 794143 Epub 2015/10/20.
[http://dx.doi.org/10.1155/2015/794143] 
[14] 
Aguiar CCd. Caracterização da dinâmica da complexação do receptor tipo Toll 4 humano a MD-2 2013. Available at:  https://lume.ufrgs.br/handle/10183/117886
[15] 
Takeda K, Akira S. Toll-Like Receptors in innate immunity. Int Immunol  2005; 17(1): 1-14.
[http://dx.doi.org/10.1093/intimm/dxh186] [PMID:  15585605] 
[16] 
Kawasaki K, Akashi S, Shimazu R, Yoshida T, Miyake K, Nishijima M. Mouse toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J Biol Chem  2000; 275(4): 2251-4.
[http://dx.doi.org/10.1074/jbc.275.4.2251] [PMID:  10644670] 
[17] 
Vidya MK, Kumar VG, Sejian V, Bagath M, Krishnan G, Bhatta R. Toll-Like Receptors: Significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol  2018; 37(1): 20-36.
[http://dx.doi.org/10.1080/08830185.2017.1380200] [PMID:  29028369] 
[18] 
Takeda K, Akira S. Toll-like receptors. Curr Protoc Immunol  2003; 21(1): 335-76.
[http://dx.doi.org/10.1002/0471142735.im1412s109] 
[19] 
Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol  2014; 5: 461.
[http://dx.doi.org/10.3389/fimmu.2014.00461] [PMID:  25309543] 
[20] 
Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell  2006; 124(4): 783-801.
[http://dx.doi.org/10.1016/j.cell.2006.02.015] [PMID:  16497588] 
[21] 
Flo TH, Ryan L, Latz E, et al. Involvement of Toll-Like Receptor (TLR) 2 and TLR4 in cell activation by mannuronic acid polymers. J Biol Chem  2002; 277(38): 35489-95.
[http://dx.doi.org/10.1074/jbc.M201366200] [PMID:  12089142] 
[22] 
Ozinsky A, Underhill DM, Fontenot JD, et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-Like Receptors. Proc Natl Acad Sci USA  2000; 97(25): 13766-71.
[http://dx.doi.org/10.1073/pnas.250476497] [PMID:  11095740] 
[23] 
Perera P-Y, Mayadas TN, Takeuchi O, et al. CD11b/CD18 acts in concert with CD14 and Toll-Like Receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression. J Immunol  2001; 166(1): 574-81.
[http://dx.doi.org/10.4049/jimmunol.166.1.574] [PMID:  11123339] 
[24] 
Medzhitov R. Toll-Like Receptors and innate immunity. Nat Rev Immunol  2001; 1(2): 135-45.
[http://dx.doi.org/10.1038/35100529] [PMID:  11905821] 
[25] 
Fuglsang A, Therkildsen P, Crone C. Presynaptic modulation of sympathetic nerve transmission-an element in vasomotor control. Int J Microcirc Clin Exp  1989; 8(1): 71-84.
[PMID:  2566586] 
[26] 
Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science  1998; 282(5396): 2085-8.
[http://dx.doi.org/10.1126/science.282.5396.2085] [PMID:  9851930] 
[27] 
Hoshino K, Takeuchi O, Kawai T, et al. Cutting edge: Toll-Like Receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol  1999; 162(7): 3749-52.
[PMID:  10201887] 
[28] 
Shimazu R, Akashi S, Ogata H, et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med  1999; 189(11): 1777-82.
[http://dx.doi.org/10.1084/jem.189.11.1777] [PMID:  10359581] 
[29] 
Nagai Y, Akashi S, Nagafuku M, et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol  2002; 3(7): 667-72.
[http://dx.doi.org/10.1038/ni809] [PMID:  12055629] 
[30] 
Miyake K, Yamashita Y, Ogata M, Sudo T, Kimoto M. RP105, a novel B cell surface molecule implicated in B cell activation, is a member of the leucine-rich repeat protein family. J Immunol  1995; 154(7): 3333-40.
[PMID:  7897216] 
[31] 
Divanovic S, Trompette A, Atabani SF, et al. Negative regulation of Toll-Like Receptor 4 signaling by the Toll-Like Receptor homolog RP105. Nat Immunol  2005; 6(6): 571-8.
[http://dx.doi.org/10.1038/ni1198] [PMID:  15852007] 
[32] 
Byrd-Leifer CA, Block EF, Takeda K, Akira S, Ding A. The role of MyD88 and TLR4 in the LPS-mimetic activity of Taxol. Eur J Immunol  2001; 31(8): 2448-57.
[http://dx.doi.org/10.1002/1521-4141(200108)31:8<2448:AID-IMMU2448>3.0.CO;2-N] [PMID:  11500829] 
[33] 
Kurt-Jones EA, Popova L, Kwinn L, et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol  2000; 1(5): 398-401.
[http://dx.doi.org/10.1038/80833] [PMID:  11062499] 
[34] 
Asea A, Rehli M, Kabingu E, et al. Novel signal transduction pathway utilized by extracellular HSP70: Role of Toll-Like Receptor (TLR) 2 and TLR4. J Biol Chem  2002; 277(17): 15028-34.
[http://dx.doi.org/10.1074/jbc.M200497200] [PMID:  11836257] 
[35] 
Ohashi K, Burkart V, Flohé S, Kolb H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the Toll-Like Receptor-4 complex. J Immunol  2000; 164(2): 558-61.
[http://dx.doi.org/10.4049/jimmunol.164.2.558] [PMID:  10623794] 
[36] 
Adachi K, Tsutsui H, Kashiwamura S, et al. Plasmodium berghei infection in mice induces liver injury by an IL-12- and toll-like receptor/myeloid differentiation factor 88-dependent mechanism. J Immunol  2001; 167(10): 5928-34.
[http://dx.doi.org/10.4049/jimmunol.167.10.5928] [PMID:  11698470] 
[37] 
Bochud P-Y, Hawn TR, Aderem A. Cutting edge: A Toll-Like Receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. J Immunol  2003; 170(7): 3451-4.
[http://dx.doi.org/10.4049/jimmunol.170.7.3451] [PMID:  12646604] 
[38] 
Uematsu S, Akira S. Toll-like receptors and innate immunity. J Mol Med (Berl)  2006; 84(9): 712-25.
[http://dx.doi.org/10.1007/s00109-006-0084-y] [PMID:  16924467] 
[39] 
Schulz O, Diebold SS, Chen M, et al. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature  2005; 433(7028): 887-92.
[http://dx.doi.org/10.1038/nature03326] [PMID:  15711573] 
[40] 
Hemmi H, Kaisho T, Takeuchi O, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol  2002; 3(2): 196-200.
[http://dx.doi.org/10.1038/ni758] [PMID:  11812998] 
[41] 
Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science  2004; 303(5663): 1529-31.
[http://dx.doi.org/10.1126/science.1093616] [PMID:  14976261] 
[42] 
Heil F, Hemmi H, Hochrein H, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science  2004; 303(5663): 1526-9.
[http://dx.doi.org/10.1126/science.1093620] [PMID:  14976262] 
[43] 
Lund JM, Alexopoulou L, Sato A, et al. Recognition of single-stranded RNA viruses by Toll-Like Receptor 7. Proc Natl Acad Sci USA  2004; 101(15): 5598-603.
[http://dx.doi.org/10.1073/pnas.0400937101] [PMID:  15034168] 
[44] 
Barrat FJ, Meeker T, Gregorio J, et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-Like Receptors and may promote systemic lupus erythematosus. J Exp Med  2005; 202(8): 1131-9.
[http://dx.doi.org/10.1084/jem.20050914] [PMID:  16230478] 
[45] 
Lau CM, Broughton C, Tabor AS, et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-Like Receptor 7 engagement. J Exp Med  2005; 202(9): 1171-7.
[http://dx.doi.org/10.1084/jem.20050630] [PMID:  16260486] 
[46] 
Vollmer J, Tluk S, Schmitz C, et al. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. J Exp Med  2005; 202(11): 1575-85.
[http://dx.doi.org/10.1084/jem.20051696] [PMID:  16330816] 
[47] 
Berland R, Fernandez L, Kari E, et al. Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity  2006; 25(3): 429-40.
[http://dx.doi.org/10.1016/j.immuni.2006.07.014] [PMID:  16973388] 
[48] 
Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity  2006; 25(3): 417-28.
[http://dx.doi.org/10.1016/j.immuni.2006.07.013] [PMID:  16973389] 
[49] 
Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol  2006; 6(11): 823-35.
[http://dx.doi.org/10.1038/nri1957] [PMID:  17063184] 
[50] 
Deane JA, Pisitkun P, Barrett RS, et al. Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation. Immunity  2007; 27(5): 801-10.
[http://dx.doi.org/10.1016/j.immuni.2007.09.009] [PMID:  17997333] 
[51] 
Gorden KK, Qiu XX, Binsfeld CC, Vasilakos JP, Alkan SS. Cutting edge: activation of murine TLR8 by a combination of imidazoquinoline immune response modifiers and polyT oligodeoxynucleotides. J Immunol  2006; 177(10): 6584-7.
[http://dx.doi.org/10.4049/jimmunol.177.10.6584] [PMID:  17082568] 
[52] 
Peng G, Guo Z, Kiniwa Y, et al. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science  2005; 309(5739): 1380-4.
[http://dx.doi.org/10.1126/science.1113401] [PMID:  16123302] 
[53] 
Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature  2000; 408(6813): 740-5.
[http://dx.doi.org/10.1038/35047123] [PMID:  11130078] 
[54] 
Krug A, Towarowski A, Britsch S, et al. Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur J Immunol  2001; 31(10): 3026-37.
[http://dx.doi.org/10.1002/1521-4141(2001010)31:10<3026:AID-IMMU3026>3.0.CO;2-H] [PMID:  11592079] 
[55] 
Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature  2002; 416(6881): 603-7.
[http://dx.doi.org/10.1038/416603a] [PMID:  11948342] 
[56] 
Pendergraft WF III, Means TK. Toll-Like Receptors, Systemic Lupus Erythematosus Systemic Lupus Erythematosus.  Elsevier 2016; pp. 143-51.
[http://dx.doi.org/10.1016/B978-0-12-801917-7.00018-8] 
[57] 
Yarovinsky F, Zhang D, Andersen JF, et al. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science  2005; 308(5728): 1626-9.
[http://dx.doi.org/10.1126/science.1109893] [PMID:  15860593] 
[58] 
Plattner F, Yarovinsky F, Romero S, et al. Toxoplasma profilin is essential for host cell invasion and TLR11-dependent induction of an interleukin-12 response. Cell Host Microbe  2008; 3(2): 77-87.
[http://dx.doi.org/10.1016/j.chom.2008.01.001] [PMID:  18312842] 
[59] 
Morger J, Bajnok J, Boyce K, et al. Naturally occurring Toll-like receptor 11 (TLR11) and Toll-Like Receptor 12 (TLR12) polymorphisms are not associated with Toxoplasma gondii infection in wild wood mice. Infect Genet Evol  2014; 26: 180-4.
[http://dx.doi.org/10.1016/j.meegid.2014.05.032] [PMID:  24910107] 
[60] 
Shi Z, Cai Z, Yu J, et al. Toll-like receptor 11 (TLR11) prevents Salmonella penetration into the murine Peyer patches. J Biol Chem  2012; 287(52): 43417-23.
[http://dx.doi.org/10.1074/jbc.M112.411009] [PMID:  23135279] 
[61] 
Signorino G, Mohammadi N, Patanè F, et al. Role of Toll-like receptor 13 in innate immune recognition of group B streptococci. Infect Immun  2014; 82(12): 5013-22.
[http://dx.doi.org/10.1128/IAI.02282-14] [PMID:  25225249] 
[62] 
Blasius AL, Arnold CN, Georgel P, et al. Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells. Proc Natl Acad Sci USA  2010; 107(46): 19973-8.
[http://dx.doi.org/10.1073/pnas.1014051107] [PMID:  21045126] 
[63] 
Yu M, Wang H, Ding A, et al. HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock  2006; 26(2): 174-9.
[http://dx.doi.org/10.1097/01.shk.0000225404.51320.82] [PMID:  16878026] 
[64] 
Ishii KJ, Coban C, Kato H, et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat Immunol  2006; 7(1): 40-8.
[http://dx.doi.org/10.1038/ni1282] [PMID:  16286919] 
[65] 
Tounai H, Hayakawa N, Kato H, Araki T. Immunohistochemical study on distribution of NF-kappaB and p53 in gerbil hippocampus after transient cerebral ischemia: effect of pitavastatin. Metab Brain Dis  2007; 22(1): 89-104.
[http://dx.doi.org/10.1007/s11011-006-9040-3] [PMID:  17226097] 
[66] 
Junjie X, Songyao J, Minmin S, et al. The association between Toll-like receptor 2 single-nucleotide polymorphisms and hepatocellular carcinoma susceptibility. BMC Cancer  2012; 12: 57.
[http://dx.doi.org/10.1186/1471-2407-12-57] [PMID:  22309608] 
[67] 
Narayanankutty V, Narayanankutty A, Nair A. Heat Shock Proteins (HSPs): A novel target for cancer metastasis prevention. Curr Drug Targets  2019; 20(7): 727-37.
[http://dx.doi.org/10.2174/1389450120666181211111815] [PMID:  30526455] 
[68] 
Narayanankutty A. PI3K/Akt/mTOR pathway as a therapeutic target for colorectal cancer: A review of preclinical and clinical evidence. Curr Drug Targets  2019; 20(12): 1217-26.
[http://dx.doi.org/10.2174/1389450120666190618123846] [PMID:  31215384] 
[69] 
Roy N, Narayanankutty A, Nazeem PA, Valsalan R, Babu TD, Mathew D. Plant phenolics ferulic acid and p-coumaric acid inhibit colorectal cancer cell proliferation through EGFR down-regulation. Asian Pac J Cancer Prev  2016; 17(8): 4019-23.
[PMID:  27644655] 
[70] 
Roy N, Nazeem PA, Babu TD, et al. EGFR gene regulation in colorectal cancer cells by garlic phytocompounds with special emphasis on S-Allyl-L-Cysteine Sulfoxide. Interdiscip Sci  2018; 10(4): 686-93.
[http://dx.doi.org/10.1007/s12539-017-0227-6] [PMID:  28349439] 
[71] 
Narayanankutty A, Job JT, Narayanankutty V. Glutathione, an antioxidant tripeptide: Dual roles in carcinogenesis and chemoprevention. Curr Protein Pept Sci  2019; 20(9): 907-17.
[http://dx.doi.org/10.2174/1389203720666190206130003] [PMID:  30727890] 
[72] 
Narayanankutty A. Toll-like receptors as a novel therapeutic target for natural products against chronic diseases. Curr Drug Targets  2019; 20(10): 1068-80.
[http://dx.doi.org/10.2174/1389450120666190222181506] [PMID:  30806312] 
[73] 
Mishra V, Pathak C. Human Toll-Like Receptor 4 (hTLR4): Structural and functional dynamics in cancer. Int J Biol Macromol  2019; 122: 425-51.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.10.142] [PMID:  30365988] 
[74] 
Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nat Rev Cancer  2009; 9(1): 57-63.
[http://dx.doi.org/10.1038/nrc2541] [PMID:  19052556] 
[75] 
Tongtawee T, Simawaranon T, Wattanawongdon W, Dechsukhum C, Leeanansaksiri W. Toll-like receptor 2 and 4 polymorphisms associated with Helicobacter pylori susceptibility and gastric cancer. Turk J Gastroenterol 2018.
[http://dx.doi.org/10.5152/tjg.2018.17461] [PMID:  30301709] 
[76] 
Chen J, Hu S, Liang S, et al. Associations between the four toll-like receptor polymorphisms and the risk of gastric cancer: a meta-analysis. Cancer Biother Radiopharm  2013; 28(9): 674-81.
[http://dx.doi.org/10.1089/cbr.2012.1395] [PMID:  24007538] 
[77] 
Castaño-Rodríguez N, Kaakoush NO, Goh KL, Fock KM, Mitchell HM. The role of TLR2, TLR4 and CD14 genetic polymorphisms in gastric carcinogenesis: a case-control study and meta-analysis. PLoS One  2013; 8(4)e60327
[http://dx.doi.org/10.1371/journal.pone.0060327] [PMID:  23565226] 
[78] 
Zhou Q, Wang C, Wang X, et al. Association between TLR4 (+896A/G and +1196C/T) polymorphisms and gastric cancer risk: an updated meta-analysis. PLoS One  2014; 9(10)e109605
[http://dx.doi.org/10.1371/journal.pone.0109605] [PMID:  25290654] 
[79] 
Tian S, Zhang L, Yang T, et al. The Associations between Toll-Like Receptor 9 gene polymorphisms and cervical cancer susceptibility. Mediators Inflamm 2018.20189127146
[http://dx.doi.org/10.1155/2018/9127146] [PMID:  30147445] 
[80] 
Pandey NO, Chauhan AV, Raithatha NS, et al. Association of TLR4 and TLR9 polymorphisms and haplotypes with cervical cancer susceptibility. Sci Rep  2019; 9(1): 9729.
[http://dx.doi.org/10.1038/s41598-019-46077-z] [PMID:  31278284] 
[81] 
Semlali A, Parine NR, Al Amri A, et al. Association between TLR-9 polymorphisms and colon cancer susceptibility in Saudi Arabian female patients. OncoTargets Ther  2016; 10: 1-11.
[http://dx.doi.org/10.2147/OTT.S106024] [PMID:  28031717] 
[82] 
Zhang L, Qin H, Guan X, Zhang K, Liu Z. The TLR9 gene polymorphisms and the risk of cancer: evidence from a meta-analysis. PLoS One  2013; 8(8)e71785
[http://dx.doi.org/10.1371/journal.pone.0071785] [PMID:  23990988] 
[83] 
Sheng WY, Yong Z, Yun Z, Hong H, Hai LL. Toll-like receptor 4 gene polymorphisms and susceptibility to colorectal cancer: a meta-analysis and review. Arch Med Sci  2015; 11(4): 699-707.
[http://dx.doi.org/10.5114/aoms.2015.53288] [PMID:  26322080] 
[84] 
Pandey N, Chauhan A, Jain N. TLR4 polymorphisms and expression in solid cancers. Mol Diagn Ther  2018; 22(6): 683-702.
[http://dx.doi.org/10.1007/s40291-018-0361-9] [PMID:  30311146] 
[85] 
Ding L, Jiang Q, Li G, et al. Comprehensive assessment of association between TLR4 gene polymorphisms and cancer risk: a systematic meta-analysis. Oncotarget  2017; 8(59): 100593-602.
[http://dx.doi.org/10.18632/oncotarget.21543] [PMID:  29246004] 
[86] 
Sun M, Geng D, Li S, Chen Z, Zhao W. LncRNA PART1 modulates toll-like receptor pathways to influence cell proliferation and apoptosis in prostate cancer cells. Biol Chem  2018; 399(4): 387-95.
[http://dx.doi.org/10.1515/hsz-2017-0255] [PMID:  29261512] 
[87] 
Wang W, Wang J. Toll-Like Receptor 4 (TLR4)/Cyclooxygenase-2 (COX-2) regulates prostate cancer cell proliferation, migration, and invasion by NF-κB Activation. Med Sci Monit  2018; 24: 5588-97.
[http://dx.doi.org/10.12659/MSM.906857] [PMID:  30098292] 
[88] 
Xu Y, Liu H, Liu S, et al. Genetic variant of IRAK2 in the toll-like receptor signaling pathway and survival of non-small cell lung cancer. Int J Cancer  2018; 143(10): 2400-8.
[http://dx.doi.org/10.1002/ijc.31660] [PMID:  29978465] 
[89] 
Park GB, Kim D. TLR5/7-mediated PI3K activation triggers epithelial-mesenchymal transition of ovarian cancer cells through WAVE3-dependent mesothelin or OCT4/SOX2 expression. Oncol Rep  2017; 38(5): 3167-76.
[http://dx.doi.org/10.3892/or.2017.5941] [PMID:  28901470] 
[90] 
Park GB, Chung YH, Kim D. Induction of galectin-1 by TLR-dependent PI3K activation enhances epithelial-mesenchymal transition of metastatic ovarian cancer cells. Oncol Rep  2017; 37(5): 3137-45.
[http://dx.doi.org/10.3892/or.2017.5533] [PMID:  28350104] 
[91] 
Kondo Y, Higa-Nakamine S, Noguchi N, et al. Induction of epithelial-mesenchymal transition by flagellin in cultured lung epithelial cells. Am J Physiol Lung Cell Mol Physiol  2012; 303(12): L1057-69.
[http://dx.doi.org/10.1152/ajplung.00096.2012] [PMID:  23064951] 
[92] 
Jing Y-Y, Han Z-P, Sun K, et al. Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide. BMC Med  2012; 10: 98.
[http://dx.doi.org/10.1186/1741-7015-10-98] [PMID:  22938142] 
[93] 
Yao R-R, Li J-H, Zhang R, Chen R-X, Wang Y-H. M2-polarized tumor-associated macrophages facilitated migration and epithelial-mesenchymal transition of HCC cells via the TLR4/STAT3 signaling pathway. World J Surg Oncol  2018; 16(1): 9.
[http://dx.doi.org/10.1186/s12957-018-1312-y] [PMID:  29338742] 
[94] 
Shi J, Li Q, Sheng M, Zheng M, Yu M, Zhang L. The role of TLR4 in M1 macrophage-induced epithelial-mesenchymal transition of peritoneal mesothelial cells. Cell Physiol Biochem  2016; 40(6): 1538-48.
[http://dx.doi.org/10.1159/000453204] [PMID:  27997892] 
[95] 
Tang S, Jiang X, Wu L, et al. Toll-like receptor 4 shRNA attenuates lipopolysaccharide-induced epithelial-mesenchymal transition of intrahepatic biliary epithelial cells in rats. Biomed Pharmacother  2018; 107: 1210-7.
[http://dx.doi.org/10.1016/j.biopha.2018.08.071] [PMID:  30257335] 
[96] 
Chung YH, Kim D. Enhanced TLR4 expression on colon cancer cells after chemotherapy promotes cell survival and epithelial-mesenchymal transition through phosphorylation of GSK3β. Anticancer Res  2016; 36(7): 3383-94.
[PMID:  27354597] 
[97] 
Zandi Z, Kashani B, Poursani EM, et al. TLR4 blockade using TAK-242 suppresses ovarian and breast cancer cells invasion through the inhibition of extracellular matrix degradation and epithelial-mesenchymal transition. Eur J Pharmacol  2019; 853: 256-63.
[http://dx.doi.org/10.1016/j.ejphar.2019.03.046] [PMID:  30930249] 
[98] 
Sun Y, Wu C, Ma J, et al. Toll-like receptor 4 promotes angiogenesis in pancreatic cancer via PI3K/AKT signaling. Exp Cell Res  2016; 347(2): 274-82.
[http://dx.doi.org/10.1016/j.yexcr.2016.07.009] [PMID:  27426724] 
[99] 
Paone A, Galli R, Gabellini C, et al. Toll-like receptor 3 regulates angiogenesis and apoptosis in prostate cancer cell lines through hypoxia-inducible factor 1 alpha. Neoplasia  2010; 12(7): 539-49.
[http://dx.doi.org/10.1593/neo.92106] [PMID:  20651983] 
[100] 
Saber T, Veale DJ, Balogh E, et al. Toll-like receptor 2 induced angiogenesis and invasion is mediated through the Tie2 signalling pathway in rheumatoid arthritis. PLoS One  2011; 6(8)e23540
[http://dx.doi.org/10.1371/journal.pone.0023540] [PMID:  21858161] 
[101] 
Thuringer D, Jego G, Wettstein G, et al. Extracellular HSP27 mediates angiogenesis through Toll-like receptor 3. FASEB J  2013; 27(10): 4169-83.
[http://dx.doi.org/10.1096/fj.12-226977] [PMID:  23804239] 
[102] 
Bhattacharjee R, Lala P. Role of toll-like receptors in COX-2 mediated VEGF-C upregulation in breast cancer. Cancer Res  2009; 69: 4139.
[103] 
Zheng Q, Xu J, Lin Z, et al. Inflammatory factor receptor Toll-like receptor 4 controls telomeres through heterochromatin protein 1 isoforms in liver cancer stem cell. J Cell Mol Med  2018; 22(6): 3246-58.
[http://dx.doi.org/10.1111/jcmm.13606] [PMID:  29602239] 
[104] 
Wang L, Zhu R, Huang Z, Li H, Zhu H. Lipopolysaccharide-induced toll-like receptor 4 signaling in cancer cells promotes cell survival and proliferation in hepatocellular carcinoma. Dig Dis Sci  2013; 58(8): 2223-36.
[http://dx.doi.org/10.1007/s10620-013-2745-3] [PMID:  23828139] 
[105] 
Zu Y, Ping W, Deng T, Zhang N, Fu X, Sun W. Lipopolysaccharide-induced toll-like receptor 4 signaling in esophageal squamous cell carcinoma promotes tumor proliferation and regulates inflammatory cytokines expression. Dis Esophagus  2017; 30(2): 1-8.
[PMID:  27061118] 
[106] 
Brenner L, Arbeit RD, Sullivan T. IMO-8400, an antagonist of toll-like receptors 7, 8, and 9, in development for genetically defined B-cell lymphomas: Safety and activity in phase 1 and phase 2 clinical trials. Blood  2014; 124: 3101.
[http://dx.doi.org/10.1182/blood.V124.21.3101.3101] 
[107] 
Bhagat L, Wang D, Jiang W, Agrawal S. Abstract 2570: IMO-8400, a selective antagonist of TLRs 7, 8 and 9, inhibits MYD88 L265P mutation-driven signaling and cell survival: A potential novel approach for treatment of B-cell lymphomas harboring MYD88 L265P mutation. Cancer Res  2014; 74: 2570.
[108] 
Liu YD, Yu L, Ying L, Balic J, Gao H, Deng NT, et al. Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2. Int J Cancer 2018.
[PMID:  30536754] 
[109] 
Huang J, Hang JJ, Qin XR, Wang XY. Interaction of H. pylori with toll-like receptor 2-196 to -174 ins/del polymorphism is associated with gastric cancer susceptibility in southern China. Int J Clin Oncol 2018.
[PMID:  30554285] 
[110] 
de Barros Gallo C, Marichalar-Mendia X, Setien-Olarra A, et al. Toll-like receptor 2 rs4696480 polymorphism and risk of oral cancer and oral potentially malignant disorder. Arch Oral Biol  2017; 82: 109-14.
[http://dx.doi.org/10.1016/j.archoralbio.2017.06.003] [PMID:  28624699] 
[111] 
Matijevic Glavan T, Cipak Gasparovic A, Vérillaud B, Busson P, Pavelic J. Toll-like receptor 3 stimulation triggers metabolic reprogramming in pharyngeal cancer cell line through Myc, MAPK, and HIF. Mol Carcinog  2017; 56(4): 1214-26.
[http://dx.doi.org/10.1002/mc.22584] [PMID:  27805282] 
[112] 
Maitra R, Augustine T, Dayan Y, Chandy C, Coffey M, Goel S. Toll like receptor 3 as an immunotherapeutic target for KRAS mutated colorectal cancer. Oncotarget  2017; 8(21): 35138-53.
[http://dx.doi.org/10.18632/oncotarget.16812] [PMID:  28422714] 
[113] 
Quan XQ, Xie ZL, Ding Y, Feng R, Zhu XY, Zhang QX. miR-198 regulated the tumorigenesis of gastric cancer by targeting Toll-like receptor 4 (TLR4). Eur Rev Med Pharmacol Sci  2018; 22(8): 2287-96.
[PMID:  29762851] 
[114] 
Chen G, Xu M, Chen J, et al. Clinicopathological features and increased expression of Toll-Like Receptor 4 of gastric cardia cancer in a high-risk chinese population. J Immunol Res 2018.20187132868
[http://dx.doi.org/10.1155/2018/7132868] [PMID:  29670922] 
[115] 
Yue Y, Zhou T, Gao Y, et al. High mobility group box 1/toll-like receptor 4/myeloid differentiation factor 88 signaling promotes progression of gastric cancer. Tumour Biol  2017; 39(3)1010428317694312
[http://dx.doi.org/10.1177/1010428317694312] [PMID:  28347236] 
[116] 
Peyret V, Nazar M, Martín M, et al. Functional toll-like receptor 4 overexpression in papillary thyroid cancer by MAPK/ERK-Induced ETS1 transcriptional activity. Mol Cancer Res  2018; 16(5): 833-45.
[http://dx.doi.org/10.1158/1541-7786.MCR-17-0433] [PMID:  29523762] 
[117] 
Ou T, Lilly M, Jiang W. The pathologic role of toll-like receptor 4 in prostate cancer. Front Immunol  2018; 9: 1188.
[http://dx.doi.org/10.3389/fimmu.2018.01188] [PMID:  29928275] 
[118] 
Khademalhosseini M, Arababadi MK. Toll-like receptor 4 and breast cancer: An updated systematic review. Breast Cancer  2019; 26(3): 265-71.
[PMID:  30543015] 
[119] 
Gao XL, Yang JJ, Wang SJ, et al. Effects of RNA interference-mediated silencing of toll-like receptor 4 gene on proliferation and apoptosis of human breast cancer MCF-7 and MDA-MB-231 cells: An in vitro study. J Cell Physiol  2018; 234(1): 433-42.
[http://dx.doi.org/10.1002/jcp.26573] [PMID:  29932226] 
[120] 
Semlali A, Jalouli M, Parine NR, et al. Toll-like receptor 4 as a predictor of clinical outcomes of estrogen receptor-negative breast cancer in Saudi women. OncoTargets Ther  2017; 10: 1207-16.
[http://dx.doi.org/10.2147/OTT.S112165] [PMID:  28280355] 
[121] 
Shuang C, Weiguang Y, Zhenkun F, et al. Toll-like receptor 5 gene polymorphism is associated with breast cancer susceptibility. Oncotarget  2017; 8(51): 88622-9.
[http://dx.doi.org/10.18632/oncotarget.20242] [PMID:  29179462] 
[122] 
Wang F, Jin R, Zou BB, et al. Activation of Toll-like receptor 7 regulates the expression of IFN-λ1, p53, PTEN, VEGF, TIMP-1 and MMP-9 in pancreatic cancer cells. Mol Med Rep  2016; 13(2): 1807-12.
[http://dx.doi.org/10.3892/mmr.2015.4730] [PMID:  26718740] 
[123] 
Shahriari S, Rezaeifard S, Moghimi HR, Khorramizadeh MR, Faghih Z. Cell membrane and intracellular expression of toll-like receptor 9 (TLR9) in colorectal cancer and breast cancer cell-lines. Cancer Biomark  2017; 18(4): 375-80.
[http://dx.doi.org/10.3233/CBM-160260] [PMID:  28106541] 
[124] 
Sandholm J, Lehtimäki J, Ishizu T, et al. Toll-like receptor 9 expression is associated with breast cancer sensitivity to the growth inhibitory effects of bisphosphonates in vitro and in vivo. Oncotarget  2016; 7(52): 87373-89.
[http://dx.doi.org/10.18632/oncotarget.13570] [PMID:  27888633] 
[125] 
Kim HJ, Park MK, Kim SY, Lee CH. Novel suppressive effects of ketotifen on migration and invasion of MDA-MB-231 and HT-1080 cancer cells. Biomol Ther (Seoul)  2014; 22(6): 540-6.
[http://dx.doi.org/10.4062/biomolther.2014.081] [PMID:  25489422] 
[126] 
Kuo W-T, Lee T-C, Yu LC-H. Eritoran suppresses colon cancer by altering a functional balance in Toll-like Receptors that bind lipopolysaccharide. Cancer Res  2016; 76(16): 4684-95.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-0172] [PMID:  27328732] 
[127] 
Jacobs VL, Landry RP, Liu Y, Romero-Sandoval EA, De Leo JA. Propentofylline decreases tumor growth in a rodent model of glioblastoma multiforme by a direct mechanism on microglia. Neuro-oncol  2012; 14(2): 119-31.
[http://dx.doi.org/10.1093/neuonc/nor194] [PMID:  22086978] 
[128] 
Kashani B, Zandi Z, Bashash D, et al. Small molecule inhibitor of TLR4 inhibits ovarian cancer cell proliferation: new insight into the anticancer effect of TAK-242 (Resatorvid). Cancer Chemother Pharmacol  2020; 85(1): 47-59.
[http://dx.doi.org/10.1007/s00280-019-03988-y] [PMID:  31786654] 
[129] 
Zandi Z, Kashani B, Bashash D, et al. The anticancer effect of the TLR4 inhibition using TAK-242 (resatorvid) either as a single agent or in combination with chemotherapy: A novel therapeutic potential for breast cancer. J Cell Biochem  2020; 121(2): 1623-34.
[http://dx.doi.org/10.1002/jcb.29397] [PMID:  31535397] 
[130] 
Biber A, Durusu İZ, Özen C. In vitro anticancer effect of tricyclic antidepressant nortriptyline on multiple myeloma. Turkish journal of biology = Turk biyoloji dergisi  2018; 42: 414-21.
[http://dx.doi.org/10.3906/biy-1802-11 ] 
[131] 
Cho JH, Lee H-J, Ko H-J, et al. The TLR7 agonist imiquimod induces anti-cancer effects via autophagic cell death and enhances anti-tumoral and systemic immunity during radiotherapy for melanoma. Oncotarget  2017; 8(15): 24932-48.
[http://dx.doi.org/10.18632/oncotarget.15326] [PMID:  28212561] 
[132] 
Aspord C, Tramcourt L, Leloup C, et al. Imiquimod inhibits melanoma development by promoting pDC cytotoxic functions and impeding tumor vascularization. J Invest Dermatol  2014; 134(10): 2551-61.
[http://dx.doi.org/10.1038/jid.2014.194] [PMID:  24751730] 
[133] 
Frank MJ, Reagan PM, Bartlett NL, et al. In Situ vaccination with a tlr9 agonist and local low-dose radiation induces systemic responses in untreated indolent lymphoma. Cancer Discov  2018; 8(10): 1258-69.
[http://dx.doi.org/10.1158/2159-8290.CD-18-0743] [PMID:  30154192] 
[134] 
Wittig B, Schmidt M, Scheithauer W, Schmoll H-J. MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: from bench to bedside. Crit Rev Oncol Hematol  2015; 94(1): 31-44.
[http://dx.doi.org/10.1016/j.critrevonc.2014.12.002] [PMID:  25577571] 
[135] 
Cho IH, Jang EH, Hong D, Jung B, Park MJ, Kim JH. Suppression of LPS-induced epithelial-mesenchymal transition by aqueous extracts of Prunella vulgaris through inhibition of the NF-κB/Snail signaling pathway and regulation of EMT-related protein expression. Oncol Rep  2015; 34(5): 2445-50.
[http://dx.doi.org/10.3892/or.2015.4218] [PMID:  26324883] 
[136] 
Hong D, Jang SY, Jang EH, et al. Shikonin as an inhibitor of the LPS-induced epithelial-to-mesenchymal transition in human breast cancer cells. Int J Mol Med  2015; 36(6): 1601-6.
[http://dx.doi.org/10.3892/ijmm.2015.2373] [PMID:  26498588] 
[137] 
Illam SP, Narayanankutty A, Mathew SE, Valsalakumari R, Jacob RM, Raghavamenon AC. Epithelial Mesenchymal Transition in Cancer Progression: Prev entive Phytochemicals. Recent Patents Anticancer Drug Discov  2017; 12(3): 234-46.
[http://dx.doi.org/10.2174/1574892812666170424150407] [PMID:  28440207] 
[138] 
Ying J, Zhou HY, Liu P, et al. Aspirin inhibited the metastasis of colon cancer cells by inhibiting the expression of toll-like receptor 4. Cell Biosci  2018; 8: 1.
[http://dx.doi.org/10.1186/s13578-017-0198-7] [PMID:  29308184] 
[139] 
Mett V, Komarova EA, Greene K, et al. Mobilan: a recombinant adenovirus carrying Toll-like receptor 5 self-activating cassette for cancer immunotherapy. Oncogene  2018; 37(4): 439-49.
[http://dx.doi.org/10.1038/onc.2017.346] [PMID:  28967901] 
[140] 
Feng Y, Mu R, Wang Z, et al. A toll-like receptor agonist mimicking microbial signal to generate tumor-suppressive macrophages. Nat Commun  2019; 10(1): 2272.
[http://dx.doi.org/10.1038/s41467-019-10354-2] [PMID:  31118418] 
[141] 
Matsumoto M, Takeda Y, Tatematsu M, Seya T. Toll-Like Receptor 3 signal in dendritic cells benefits cancer immunotherapy. Front Immunol  2017; 8: 1897.
[http://dx.doi.org/10.3389/fimmu.2017.01897] [PMID:  29312355] 
[142] 
Takeda Y, Kataoka K, Yamagishi J, Ogawa S, Seya T, Matsumoto MA. TLR3-Specific adjuvant relieves innate resistance to PD-L1 blockade without cytokine toxicity in tumor vaccine immunotherapy. Cell Rep  2017; 19(9): 1874-87.
[http://dx.doi.org/10.1016/j.celrep.2017.05.015] [PMID:  28564605] 
[143] 
Ribas A, Medina T, Kummar S, et al. SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study. Cancer Discov  2018; 8(10): 1250-7.
[http://dx.doi.org/10.1158/2159-8290.CD-18-0280] [PMID:  30154193] 
[144] 
Kapp K, Volz B, Curran MA, Oswald D, Wittig B, Schmidt M. EnanDIM - a novel family of L-nucleotide-protected TLR9 agonists for cancer immunotherapy. J Immunother Cancer  2019; 7(1): 5.
[http://dx.doi.org/10.1186/s40425-018-0470-3] [PMID:  30621769] 
[145] 
Smith M, García-Martínez E, Pitter MR, et al. Trial Watch: Toll-like receptor agonists in cancer immunotherapy. OncoImmunology  2018; 7(12)e1526250
[http://dx.doi.org/10.1080/2162402X.2018.1526250] [PMID:  30524908] 
[146] 
Adams S, Kozhaya L, Martiniuk F, et al. Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer. Clin Cancer Res  2012; 18(24): 6748-57.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-1149] [PMID:  22767669] 
[147] 
Pasadyn SR, Cain R. Topical imiquimod induces severe weakness and myalgias after three applications: a case report. J Clin Aesthet Dermatol  2019; 12(6): 58-9.
[PMID:  31360290] 
[148] 
Caperton C, Berman B. Safety, efficacy, and patient acceptability of imiquimod for topical treatment of actinic keratoses. Clin Cosmet Investig Dermatol  2011; 4: 35-40.
[PMID:  21691565] 
[149] 
Levy R, Reagan PM, Friedberg JW, et al. SD-101, a novel class c cpg-oligodeoxynucleotide (ODN) Toll-Like Receptor 9 (TLR9) agonist, given with low dose radiation for untreated low grade b-cell lymphoma: interim results of a phase 1/2 trial. Blood  2016; 128: 2974.
[http://dx.doi.org/10.1182/blood.V128.22.2974.2974] 
[150] 
Deguchi A, Tomita T, Ohto U, et al. Eritoran inhibits S100A8-mediated TLR4/MD-2 activation and tumor growth by changing the immune microenvironment. Oncogene  2016; 35(11): 1445-56.
[http://dx.doi.org/10.1038/onc.2015.211] [PMID:  26165843] 
[151] 
Kashani B, Zandi Z, Karimzadeh MR, Bashash D, Nasrollahzadeh A, Ghaffari SH. Blockade of TLR4 using TAK-242 (resatorvid) enhances anti-cancer effects of chemotherapeutic agents: a novel synergistic approach for breast and ovarian cancers. Immunol Res  2019; 67(6): 505-16.
[http://dx.doi.org/10.1007/s12026-019-09113-8] [PMID:  32026322] 
[152] 
Janda J, Burkett NB, Blohm-Mangone K, et al. Resatorvid-based pharmacological antagonism of cutaneous TLR4 blocks UV-induced NF-κB and AP-1 signaling in keratinocytes and mouse skin. Photochem Photobiol  2016; 92(6): 816-25.
[http://dx.doi.org/10.1111/php.12659] [PMID:  27859308] 
[153] 
Blohm-Mangone K, Burkett NB, Tahsin S, et al. Pharmacological TLR4 antagonism using topical resatorvid blocks solar UV-induced skin tumorigenesis in SKH-1 Mice. Cancer Prev Res (Phila)  2018; 11(5): 265-78.
[http://dx.doi.org/10.1158/1940-6207.CAPR-17-0349] [PMID:  29437671] 
[154] 
Xu Y, Chen S, Cao Y, Zhou P, Chen Z, Cheng K. Discovery of novel small molecule TLR4 inhibitors as potent anti-inflammatory agents. Eur J Med Chem  2018; 154: 253-66.
[http://dx.doi.org/10.1016/j.ejmech.2018.05.033] [PMID:  29807331] 
[155] 
Huang KM, Liang S, Yeung S, et al. Topically applied carvedilol attenuates solar ultraviolet radiation induced skin carcinogenesis. Cancer Prev Res (Phila)  2017; 10(10): 598-606.
[http://dx.doi.org/10.1158/1940-6207.CAPR-17-0132] [PMID:  28912118] 
[156] 
Lewis SS, Loram LC, Hutchinson MR, et al. (+)-naloxone, an opioid-inactive Toll-Like Receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats. J Pain  2012; 13(5): 498-506.
[http://dx.doi.org/10.1016/j.jpain.2012.02.005] [PMID:  22520687] 
[157] 
Bimonte S, Barbieri A, Cascella M, et al. The effects of naloxone on human breast cancer progression: in vitro and in vivo studies on MDA.MB231 cells. OncoTargets Ther  2018; 11: 185-91.
[http://dx.doi.org/10.2147/OTT.S145780] [PMID:  29379300] 
[158] 
Bimonte S, Barbieri A, Cascella M, et al. Naloxone counteracts the promoting tumor growth effects induced by morphine in an animal model of triple-negative breast cancer. In Vivo  2019; 33(3): 821-5.
[http://dx.doi.org/10.21873/invivo.11545] [PMID:  31028203] 
[159] 
Zhang Z, Du X, Zhao C, Cao B, Zhao Y, Mao X. The antidepressant amitriptyline shows potent therapeutic activity against multiple myeloma. Anticancer Drugs  2013; 24(8): 792-8.
[http://dx.doi.org/10.1097/CAD.0b013e3283628c21] [PMID:  23708819] 
[160] 
Barochia A, Solomon S, Cui X, Natanson C, Eichacker PQ. Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies. Expert Opin Drug Metab Toxicol  2011; 7(4): 479-94.
[http://dx.doi.org/10.1517/17425255.2011.558190] [PMID:  21323610] 
[161] 
Rice TW, Wheeler AP, Bernard GR, et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med  2010; 38(8): 1685-94.
[http://dx.doi.org/10.1097/CCM.0b013e3181e7c5c9] [PMID:  20562702] 
[162] 
Park SJ, Lee MY, Son BS, Youn HS. TBK1-targeted suppression of TRIF-dependent signaling pathway of Toll-Like Receptors by 6-shogaol, an active component of ginger. Biosci Biotechnol Biochem  2009; 73(7): 1474-8.
[http://dx.doi.org/10.1271/bbb.80738] [PMID:  19584560] 
[163] 
Kim SY, Koo JE, Seo YJ, et al. Suppression of Toll-Like Receptor 4 activation by caffeic acid phenethyl ester is mediated by interference of LPS binding to MD2. Br J Pharmacol  2013; 168(8): 1933-45.
[http://dx.doi.org/10.1111/bph.12091] [PMID:  23231684] 
[164] 
Park SJ, Youn HS. Suppression of homodimerization of Toll-Like Receptor 4 by isoliquiritigenin. Phytochemistry  2010; 71(14-15): 1736-40.
[http://dx.doi.org/10.1016/j.phytochem.2010.07.008] [PMID:  20701936] 
[165] 
Kim J-Y, Park SJ, Yun K-J, Cho Y-W, Park H-J, Lee K-T. Isoliquiritigenin isolated from the roots of Glycyrrhiza uralensis inhibits LPS-induced iNOS and COX-2 expression via the attenuation of NF-kappaB in RAW 264.7 macrophages. Eur J Pharmacol  2008; 584(1): 175-84.
[http://dx.doi.org/10.1016/j.ejphar.2008.01.032] [PMID:  18295200] 
[166] 
Koo JE, Park ZY, Kim ND, Lee JY. Sulforaphane inhibits the engagement of LPS with TLR4/MD2 complex by preferential binding to Cys133 in MD2. Biochem Biophys Res Commun  2013; 434(3): 600-5.
[http://dx.doi.org/10.1016/j.bbrc.2013.03.123] [PMID:  23583403] 
[167] 
Xu Y, Wang G, Li C, et al. Pu-erh tea reduces nitric oxide levels in rats by inhibiting inducible nitric oxide synthase expression through Toll-Like Receptor 4. Int J Mol Sci  2012; 13(6): 7174-85.
[http://dx.doi.org/10.3390/ijms13067174] [PMID:  22837686] 
[168] 
Zimmer SM, Liu J, Clayton JL, Stephens DS, Snyder JP. Paclitaxel binding to human and murine MD-2. J Biol Chem  2008; 283(41): 27916-26.
[http://dx.doi.org/10.1074/jbc.M802826200] [PMID:  18650420] 
[169] 
Zhang D, Li Y, Liu Y, Xiang X, Dong Z. Paclitaxel ameliorates lipopolysaccharide-induced kidney injury by binding myeloid differentiation protein-2 to block Toll-Like Receptor 4-mediated nuclear factor-κB activation and cytokine production. J Pharmacol Exp Ther  2013; 345(1): 69-75.
[http://dx.doi.org/10.1124/jpet.112.202481] [PMID:  23318472] 
[170] 
Gradisar H, Keber MM, Pristovsek P, Jerala R. MD-2 as the target of curcumin in the inhibition of response to LPS. J Leukoc Biol  2007; 82(4): 968-74.
[http://dx.doi.org/10.1189/jlb.1206727] [PMID:  17609337] 
[171] 
Park SH, Kyeong MS, Hwang Y, Ryu SY, Han SB, Kim Y. Inhibition of LPS binding to MD-2 co-receptor for suppressing TLR4-mediated expression of inflammatory cytokine by 1-dehydro-10-gingerdione from dietary ginger. Biochem Biophys Res Commun  2012; 419(4): 735-40.
[http://dx.doi.org/10.1016/j.bbrc.2012.02.091] [PMID:  22387540] 
[172] 
Schröfelbauer B, Raffetseder J, Hauner M, Wolkerstorfer A, Ernst W, Szolar OH. Glycyrrhizin, the main active compound in liquorice, attenuates pro-inflammatory responses by interfering with membrane-dependent receptor signalling. Biochem J  2009; 421(3): 473-82.
[http://dx.doi.org/10.1042/BJ20082416] [PMID:  19442240] 
[173] 
Hutchinson MR, Loram LC, Zhang Y, et al. Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity. Neuroscience  2010; 168(2): 551-63.
[http://dx.doi.org/10.1016/j.neuroscience.2010.03.067] [PMID:  20381591] 
[174] 
Okamoto M, Oh-E G, Oshikawa T, et al. Toll-like receptor 4 mediates the antitumor host response induced by a 55-kilodalton protein isolated from Aeginetia indica L., a parasitic plant. Clin Diagn Lab Immunol  2004; 11(3): 483-95.
[http://dx.doi.org/10.1128/CDLI.11.3.483-495.2004] [PMID:  15138173] 
[175] 
Lin FY, Chen YH, Chen YL, et al. Ginkgo biloba extract inhibits endotoxin-induced human aortic smooth muscle cell proliferation via suppression of Toll-Like Receptor 4 expression and NADPH oxidase activation. J Agric Food Chem  2007; 55(5): 1977-84.
[http://dx.doi.org/10.1021/jf062945r] [PMID:  17266329] 
[176] 
Cai Z, Sanchez A, Shi Z, Zhang T, Liu M, Zhang D. Activation of Toll-Like Receptor 5 on breast cancer cells by flagellin suppresses cell proliferation and tumor growth. Cancer Res  2011; 71(7): 2466-75.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-1993] [PMID:  21427357] 
[177] 
Roy N, Davis S, Narayanankutty A, et al. Garlic phytocompounds possess anticancer activity by specifically targeting breast cancer biomarkers - an in silico study. Asian Pac J Cancer Prev  2016; 17(6): 2883-8.
[PMID:  27356707] 
[178] 
Rana M, Maurya P, Reddy SS, et al. A standardized chemically modified curcuma longa extract modulates IRAK-MAPK signaling in inflammation and potentiates cytotoxicity. Front Pharmacol  2016; 7: 223.
[http://dx.doi.org/10.3389/fphar.2016.00223] [PMID:  27504095] 
[179] 
Li PM, Li YL, Liu B, Wang WJ, Wang YZ, Li Z. Curcumin inhibits MHCC97H liver cancer cells by activating ROS/TLR-4/caspase signaling pathway. Asian Pac J Cancer Prev  2014; 15(5): 2329-34.
[http://dx.doi.org/10.7314/APJCP.2014.15.5.2329] [PMID:  24716979] 
[180] 
Chen X, Chang L, Qu Y, Liang J, Jin W, Xia X. Tea polyphenols inhibit the proliferation, migration, and invasion of melanoma cells through the down-regulation of TLR4. Int J Immunopathol Pharmacol  2018; •••32394632017739531
[http://dx.doi.org/10.1177/0394632017739531] [PMID:  29359608] 
[181] 
Mukherjee S, Siddiqui MA, Dayal S, Ayoub YZ, Malathi K. Epigallocatechin-3-gallate suppresses proinflammatory cytokines and chemokines induced by Toll-Like Receptor 9 agonists in prostate cancer cells. J Inflamm Res  2014; 7: 89-101.
[PMID:  24971028] 
[182] 
Zhu J, Ghosh A, Coyle EM, et al. Differential effects of phenethyl isothiocyanate and D,L-sulforaphane on TLR3 signaling. J Immunol  2013; 190(8): 4400-7.
[http://dx.doi.org/10.4049/jimmunol.1202093] [PMID:  23509350] 
[183] 
Lu H, Yang Y, Gad E, et al. Polysaccharide krestin is a novel TLR2 agonist that mediates inhibition of tumor growth via stimulation of CD8 T cells and NK cells. Clin Cancer Res  2011; 17(1): 67-76.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-1763] [PMID:  21068144] 
[184] 
Plummer S, Manning T, Baker T, et al. Isolation, analytical measurements, and cell line studies of the iron-bryostatin-1 complex. Bioorg Med Chem Lett  2016; 26(10): 2489-97.
[http://dx.doi.org/10.1016/j.bmcl.2016.03.099] [PMID:  27068183] 
[185] 
Ariza ME, Ramakrishnan R, Singh NP, Chauhan A, Nagarkatti PS, Nagarkatti M. Bryostatin-1, a naturally occurring antineoplastic agent, acts as a Toll-Like Receptor 4 (TLR-4) ligand and induces unique cytokines and chemokines in dendritic cells. J Biol Chem  2011; 286(1): 24-34.
[http://dx.doi.org/10.1074/jbc.M110.135921] [PMID:  21036898] 
[186] 
Koizumi S, Masuko K, Wakita D, et al. Extracts of Larix Leptolepis effectively augments the generation of tumor antigen-specific cytotoxic T lymphocytes via activation of dendritic cells in TLR-2 and TLR-4-dependent manner. Cell Immunol  2012; 276(1-2): 153-61.
[http://dx.doi.org/10.1016/j.cellimm.2012.05.002] [PMID:  22677561 ] 
Cite As
Current Pharmaceutical Design

Targeting Toll like Receptors in Cancer: Role of TLR Natural and Synthetic Modulators

Abstract
