Abstract
C–C motif chemokine ligand 2 (CCL2) is a small cytokine that functions in inflammation and cancer development. Bindarit, a CCL2 inhibitor, is a small anti-inflammatory molecule proven safe by phase II trials in type 2 diabetic nephropathy patients. As cancer-related inflammation is a cause of pain, we investigated whether Bindarit suppresses cancer-related inflammation and pain. We established a bone-cancer mouse model by inoculating cancer cells. After applying Bindarit, we preformed pain sensitivity tests and checked cancer development by X-ray. Using flow cytometry and qRT-PCR assays, we assessed the effect of Bindarit on peripheral blood monocyte mobilization and M2 macrophage polarization. We also investigated the targets of Bindarit using western blotting and luciferase assay. Bindarit-treated mice performed better in pain sensitivity tests compare to control mice. X-ray imaging showed that Bindarit-treated mice had fewer cancer cell colonies and smaller overall tumor burden. Bindarit reduced the number of monocytes in peripheral blood and down-regulated the expression of M2 macrophage polarization makers. Bindarit also inhibited IKKβ phosphorylation. Bindarit efficiently relieves cancer-related pain and suppresses cancer development. Bindarit inhibits monocyte mobilization in peripheral blood as well as M2 macrophage polarization. IKKβ is identified as a target of Bindarit.
Similar content being viewed by others
References
Baggiolini M, Dahinden CA (1994) CC chemokines in allergic inflammation. Immunol Today 15:127–133
Ble A, Mosca M, Di Loreto G et al (2011) Antiproteinuric effect of chemokine C–C motif ligand 2 inhibition in subjects with acute proliferative lupus nephritis. Am J Nephrol 34:367–372
Boekhoudt GH, Guo Z, Beresford GW et al (2003) Communication between NF-kappa B and Sp1 controls histone acetylation within the proximal promoter of the monocyte chemoattractant protein 1 gene. J Immunol 170:4139–4147
Caronni N, Savino B, Bonecchi R (2015) Myeloid cells in cancer-related inflammation. Immunobiology 220:249–253
Carr MW, Roth SJ, Luther E, Rose SS et al (1994) Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci USA 91:3652–3656
Conductier G, Blondeau N, Guyon A et al (2010) The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol 224:93–100
Fabene PF, Bramanti P, Constantin G (2010) The emerging role for chemokines in epilepsy. J Neuroimmunol 224:22–27
Foresti ML, Arisi GM, Katki K et al (2009) Chemokine CCL2 and its receptor CCR2 are increased in the hippocampus following pilocarpine-induced status epilepticus. J Neuroinflammation 6:40
Gerard C, Rollins BJ (2001) Chemokines and disease. Nat Immunol 2:108–115
Guglielmotti A, Silvestrini B, Saso L et al (1993) Chronic inflammatory response in the rat can be blocked by bindarit. Biochem Mol Biol Int 29:747–756
Guglielmotti A, D’Onofrio E, Coletta I et al (2002) Amelioration of rat adjuvant arthritis by therapeutic treatment with bindarit, an inhibitor of MCP-1 and TNF-alpha production. Inflamm Res 51:252–258
Hickman SE, El Khoury J (2010) Mechanisms of mononuclear phagocyte recruitment in Alzheimer’s disease. CNS Neurol Disord Drug Targets 9:168–173
Ialenti A et al (2011) Inhibition of in-stent stenosis by oral administration of bindarit in porcine coronary arteries. Arterioscler Thromb Vasc Biol 31:2448–2454
Kim JS, Gautam SC, Chopp M et al (1995) Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 after focal cerebral ischemia in the rat. J Neuroimmunol 56:127–134
Lloyd CM, Dorf ME, Proudfoot A et al (1997) Role of MCP-1 and RANTES in inflammation and progression to fibrosis during murine crescentic nephritis. J Leukoc Biol 62:676–680
Lu Y, Jiang BC, Cao DL et al (2014) TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-alpha and IL-1beta signaling. Pain 155:2618–2629
Luster AD, Rothenberg ME (1997) Role of the monocyte chemoattractant protein and eotaxin subfamily of chemokines in allergic inflammation. J Leukoc Biol 62:620–633
Mantovani A, Ming WJ, Balotta C et al (1986) Origin and regulation of tumor-associated macrophages: the role of tumor-derived chemotactic factor. Biochim Biophys Acta 865:59–67
Mills CD, Lenz LL, Harris RA (2016) A breakthrough: macrophage-directed cancer immunotherapy. Cancer Res 76:513–516
Mirolo M, Fabbri M, Sironi M et al (2008) Impact of the anti-inflammatory agent bindarit on the chemokinome: selective inhibition of the monocyte chemotactic proteins. Eur Cytokine Netw 19:119–122
Mora E, Guglielmotti A, Biondi G et al (2012) Bindarit: an anti-inflammatory small molecule that modulates the NFkappaB pathway. Cell Cycle 11:159–169
Ping D, Boekhoudt G, Zhang F et al (2000) Sp1 binding is critical for promoter assembly and activation of the MCP-1 gene by tumor necrosis factor. J Biol Chem 275:1708–1714
Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51
Ramnath RD, Ng SW, Guglielmotti A et al (2008) Role of MCP-1 in endotoxemia and sepsis. Int Immunopharmacol 8:810–818
Ransohoff RM, Hamilton TA, Tani M et al (1993) Astrocyte expression of mRNA encoding cytokines IP-10 and JE/MCP-1 in experimental autoimmune encephalomyelitis. FASEB J 7:592–600
Roca H, Varsos ZS, Pienta KJ (2009a) CCL2 is a negative regulator of AMP-activated protein kinase to sustain mTOR complex-1 activation, survivin expression, and cell survival in human prostate cancer PC3 cells. Neoplasia 11:1309–1317
Roca H, Varsos ZS, Sud S et al (2009b) CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem 284:34342–34354
Ruggenenti P, Perna A, Tonelli M et al (2010) Effects of add-on fluvastatin therapy in patients with chronic proteinuric nephropathy on dual renin-angiotensin system blockade: the ESPLANADE trial. Clin J Am Soc Nephrol 5:1928–1938
Sanford DE, Belt BA, Panni RZ et al (2013) Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res 19:3404–3415
Semple BD, Bye N, Rancan M et al (2010a) Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2−/− mice. J Cereb Blood Flow Metab 30:769–782
Semple BD, Kossmann T, Morganti-Kossmann MC (2010b) Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J Cereb Blood Flow Metab 30:459–473
Xia M, Sui Z (2009) Recent developments in CCR2 antagonists. Expert Opin Ther Pat 19:295–303
Xu LL, Warren MK, Rose WL et al (1996) Human recombinant monocyte chemotactic protein and other C-C chemokines bind and induce directional migration of dendritic cells in vitro. J Leukoc Biol 60:365–371
Zoja C, Corna D, Benedetti G et al (1998) Bindarit retards renal disease and prolongs survival in murine lupus autoimmune disease. Kidney Int 53:726–734
Acknowledgements
This work was supported by the Youth Fund of the Second Hospital of Shandong University (Y2013010049) and the Fund of Science and Technology Development Projects of Shandong Provence (No. 2012GSF11849).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Research involving human participants and/or animals
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
About this article
Cite this article
Liu, S., Gao, H., Gao, C. et al. Bindarit Attenuates Pain and Cancer-Related Inflammation by Influencing Myeloid Cells in a Model of Bone Cancer. Arch. Immunol. Ther. Exp. 66, 221–229 (2018). https://doi.org/10.1007/s00005-017-0497-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00005-017-0497-z