ISO-1 is a cell-permeable isoxazoline class macrophage migration inhibitory factor (MIF) antagonist (IC50=7μM). ISO-1 binds to the catalytic active site of MIF and inhibits its D-dopachrome tautomerase activity, and down-regulates the production of TNFα, PGE2 and COX-2 in human monocytes. ISO-1 can be used for related research on sepsis, immune inflammatory diabetes, asthma airway remodeling, experimental autoimmune uveoretinitis, retinal detachment, pancreatic cancer and colorectal cancer[1-4].
In vitro, treatment of gallbladder cancer cells with 0-500µM ISO-1 for 48 hours decreased cell viability, and reduced colony formation ability and invasive ability[5]. Pretreatment with 7µM ISO-1 for 1 hour improved the survival rate of PC12 cells exposed to β-amyloid 1-40, reduced detached cells and cell debris, and promoted the extension and increase of neurite-like processes[6]. Treatment of PANC-1 human pancreatic cancer cells with 200-3200µM ISO-1 for 48-96 hours inhibited cell proliferation, inhibited cell migration, and down-regulated the mRNA expression of MIF, NF-κB p65 and TNF-α[7].
In vivo, a single intraperitoneal injection of 3mg/kg ISO-1 in perioperative ischemic stroke (PIS) mice 2 hours before distal middle cerebral artery occlusion (dMCAO) reduced infarct volume, decreased IgG extravasation, restored tight junction protein ZO-1 expression, and improved Garcia neurological function scores[8]. Intraperitoneal injection of 35mg/kg ISO-1 for 6 consecutive weeks in ovalbumin-sensitized and challenged C57BL/6 mice reduced eosinophils, lymphocytes and total cell counts in bronchoalveolar lavage fluid, decreased lung tissue inflammatory cell infiltration, reduced airway wall area, alleviated airway smooth muscle hypertrophy, decreased subepithelial collagen deposition, and reduced goblet cell hyperplasia[9]. Intraperitoneal injection of 35mg/kg ISO-1 twice daily for 3 consecutive days starting 24 hours after cecal ligation and puncture in BALB/c mice increased the survival rate of mice with polymicrobial sepsis[10].
References:
[1] Ji W, Ren Y, Wei X, et al. Ischemic stroke protected by ISO-1 inhibition of apoptosis via mitochondrial pathway. Sci Rep. 2023 Feb 16;13(1):2788.
[2] Al-Abed Y, VanPatten S. MIF as a disease target: ISO-1 as a proof-of-concept therapeutic. Future Med Chem. 2011 Jan;3(1):45-63.
[3] Liu Y, Liu Y, Wang Q, et al. MIF inhibitor ISO-1 alleviates severe acute pancreatitis-associated acute kidney injury by suppressing the NLRP3 inflammasome signaling pathway. Int Immunopharmacol. 2021 Jul;96:107555.
[4] Li T, Qu J, Hu C, et al. Macrophage migration inhibitory factor (MIF) suppresses mitophagy through disturbing the protein interaction of PINK1-Parkin in sepsis-associated acute kidney injury. Cell Death Dis. 2024 Jul 2;15(7):473.
[5] Subbannayya T, Leal-Rojas P, Barbhuiya MA, et al. Macrophage migration inhibitory factor- a therapeutic target in gallbladder cancer. BMC Cancer. 2015 Nov 4;15:843.
[6] Yu M, Zang D, Xu Y, et al. Protective effect of ISO-1 against advanced glycation end product aggravation of PC12 cell injury induced by Aβ1-40. Mol Med Rep. 2019;20(3):2135-2142.
[7] Cheng B, Wang Q, Song Y, et al. MIF inhibitor, ISO-1, attenuates human pancreatic cancer cell proliferation, migration and invasion in vitro, and suppresses xenograft tumour growth in vivo. Sci Rep. 2020 Apr 21;10:6741.
[8] Li Y, Zou C, Chen C, et al. Myeloid-derived MIF drives RIPK1-mediated cerebrovascular endothelial cell death to exacerbate ischemic brain injury. Proc Natl Acad Sci U S A. 2023 Jan 24;120(5):e2219091120.
[9] Chen PF, Luo YL, Wang W, et al. ISO-1, a macrophage migration inhibitory factor antagonist, inhibits airway remodeling in a murine model of chronic asthma. Mol Med. 2010 Sep-Oct;16(9-10):400-408.
[10] Al-Abed Y, Dabideen D, Aljabari B, et al. ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis. J Biol Chem. 2005 Nov 4;280(44):36541-36544.