SR 18292 is an inhibitor of peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α), which promotes PGC-1α acetylation, inhibits the expression of gluconeogenic genes, and reduces glucose production in hepatocytes [1]. SR 18292 enhances the interaction between histone acetyltransferase (GCN5) and PGC-1α, subsequently leading to increased PGC-1α acetylation [2]. SR 18292 reduces mitochondrial function and the expression of mitochondrial biogenesis parameters (PGC-1α, NRF2, Tfam) [3].
In vitro, SR 18292 (12.5-200μM) treatment of melanoma A375 and WM115 adherent cells for 48h dose-dependently reduced cell viability, colony formation and migration, and inhibited melanoma cell sphere formation ability and ABCG2 enrichment[4]. SR 18292 (10, 20 μM) treatment of human bone marrow-derived mesenchymal stem cells (hMSC) significantly inhibited the protein level of PGC-1α and increased the protein level of GLUT1, and increased the glucose uptake rate and lactate production rate of hMSC[5]. SR 18292 (20 μM) treatment of NK cells for 48 h or 10 days reversed the increase in cellular IFNγ, mitochondrial mass, membrane potential and glucose uptake induced by docosahexaenoic acid (DHA)[6].
In vivo, SR 18292 (10 mg/kg/day) was treated by intraperitoneal injection in sickle cell disease (SCD) mice for 4 weeks, which significantly reduced the number of irreversibly sickled erythrocytes and reticulocytes in the peripheral blood of mice and improved erythrocyte survival[7]. SR 18292 (30 μg) was treated by intrathecal injection in rats with neuropathic pain (PINP) model, and partially eliminated the analgesic effect of formoterol on PINP[8].
References:
[1] Sharabi K, Lin H, Tavares C D J, et al. Selective chemical inhibition of PGC-1α gluconeogenic activity ameliorates type 2 diabetes[J]. Cell, 2017, 169(1): 148-160. e15.
[2] Yang Y N, Zhang M Q, Yu F L, et al. Peroxisom proliferator-activated receptor-γ coactivator-1α in neurodegenerative disorders: A promising therapeutic target[J]. Biochemical Pharmacology, 2023: 115717.
[3] Xie K, Wang Y, Yin L, et al. Hydrogen gas alleviates sepsis-induced brain injury by improving mitochondrial biogenesis through the activation of PGC-α in mice[J]. Shock, 2021, 55(1): 100-109.
[4] Fontana F, Macchi C, Anselmi M, et al. PGC1-α-driven mitochondrial biogenesis contributes to a cancer stem cell phenotype in melanoma[J]. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2024, 1870(1): 166897.
[5] Jiang B, Huang L, Tian T, et al. IRX5 promotes adipogenesis of hMSCs by repressing glycolysis[J]. Cell Death Discovery, 2022, 8(1): 204.
[6] Wu S, Peng H, Li S, et al. The ω-3 polyunsaturated fatty acid docosahexaenoic acid enhances NK-cell antitumor effector functions[J]. Cancer Immunology Research, 2024, 12(6): 744-758.
[7] Sun Y, Benmhammed H, Al Abdullatif S, et al. PGC-1α agonism induces fetal hemoglobin and exerts antisickling effects in sickle cell disease[J]. Science Advances, 2024, 10(31): eadn8750.
[8] Chen N, Ge M M, Li D Y, et al. β2-adrenoreceptor agonist ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain via induction of mitochondrial biogenesis[J]. Biomedicine & pharmacotherapy, 2021, 144: 112331.
SR 18292是一种过氧化物酶体增殖物激活受体γ（PPARγ）共激活因子-1α（PGC-1α）的抑制剂，可促进PGC-1α乙酰化，抑制糖异生基因的表达，并减少肝细胞中葡萄糖的产生[1]。SR 18292可增强组蛋白乙酰转移酶（GCN5）和PGC-1α之间的相互作用，随后导致PGC-1α乙酰化增加[2]。SR 18292可降低线粒体功能和线粒体生物发生参数（PGC-1α、NRF2、Tfam）的表达[3]。
在体外，SR 18292（12.5-200μM）处理黑色素瘤A375和WM115贴壁细胞48h，剂量依赖性地降低了细胞的活力、集落形成和迁移，抑制了黑色素瘤细胞球形成能力和ABCG2富集[4]。SR 18292（10、20μM）处理人骨髓源性间充质干细胞（hMSC），显著抑制PGC-1α的蛋白水平并增加GLUT1的蛋白水平，增加了hMSC的葡萄糖摄取率和乳酸生成率[5]。SR 18292（20μM）处理NK细胞48h或10d，可逆转二十二碳六烯酸（DHA）诱导的细胞IFNγ、线粒体质量、膜电位和葡萄糖摄取增加[6]。
在体内，SR 18292（10mg/kg/day）通过腹腔注射治疗镰状细胞病（SCD）小鼠4周，显著减少了小鼠的外周血中不可逆镰状红细胞和网织红细胞数量，改善了红细胞存活率[7]。SR 18292（30μg）通过鞘内注射处理神经性疼痛（PINP）模型大鼠，部分消除了福莫特罗对PINP的镇痛作用[8]。