Nonactin is a macrotetrolide antibiotic and mitochondrial oxidative phosphorylation uncoupler[1][2]. Nonactin inhibits recombinant human adenine nucleotide translocase (ANT) isoforms ANT1–4 with IC50 values of 4.4, 3.3, 4.7, and 3.3μM, respectively[3]. Nonactin is commonly used in studies of oxidative-phosphorylation uncoupling, ionophore mechanisms, and apoptosis in β-catenin-mutant tumors[4].
In vitro, treatment of BHK cells with Nonactin (5μg/ml; 12-14h) blocks cell-surface expression of NDV-HN and VSV-G glycoproteins without reducing their total synthesis, causes intracellular accumulation of VSV-G, inhibits syncytium formation and lowers infectious-virus yield[5]. Treatment of medullary thyroid carcinoma TT cells with Nonactin (0.12-0.5µM; 72h) reduces RET protein and mRNA level, suppresses pAKT/pmTOR signaling, induces G1 arrest, lowers cyclin D1/E, E2F1 and BCL-2, increases γH2AX and cleaved PARP, and elevates caspase-3/7 activity[6].
In vivo, Nonactin (100mg/kg/day; i.p.; 4 days) induced marked tumor regression and robust TUNEL-positive apoptosis in β-catenin-mutant HCT 116 xenograft mice without significant body-weight loss[7].
References:
[1] Pampaloni F, Mayer B, Kabat Vel-Job K, et al. A Novel Cellular Spheroid-Based Autophagy Screen Applying Live Fluorescence Microscopy Identifies Nonactin as a Strong Inducer of Autophagosomal Turnover. SLAS Discov. 2017;22(5):558-570.
[2] Martínez-Haya B, Avilés-Moreno JR, Hamad S, Elguero J. On the ionophoric selectivity of nonactin and related macrotetrolide derivatives. Phys Chem Chem Phys. 2017;19(2):1288-1297.
[3] Zhang Y, Tian D, Matsuyama H, et al. Human Adenine Nucleotide Translocase (ANT) Modulators Identified by High-Throughput Screening of Transgenic Yeast. J Biomol Screen. 2016;21(4):381-390.
[4] Hu J, Zhang J, He J. Structures, Synthesis and Biological Activities of Nonactic Acid and Its Derivatives. Curr Med Chem. 2021;28(42):8673-8691.
[5] Lee JM, Kim JG, Kim TH, et al. Nonactin hinders intracellular glycosylation in virus-infected baby hamster kidney cells. Mol Med Rep. 2010;3(1):115-119.
[6] Alqahtani T, Alsubait A, Aloumi M, et al. A novel role for nonactin: interfering with G-quadruplex in RET-driven medullary thyroid cancer. BMC Cancer. 2024;24(1):1569.
[7] Shikata Y, Kiga M, Futamura Y, et al. Mitochondrial uncoupler exerts a synthetic lethal effect against β-catenin mutant tumor cells. Cancer Sci. 2017;108(4):772-784.
Nonactin是一种大环四内酯类抗生素和线粒体氧化磷酸化解偶联剂[1][2]。Nonactin可抑制重组人腺嘌呤核苷转运酶（ANT）亚型 ANT1-4，IC50分别4.4、3.3、4.7 和 3.3μM[3]。Nonactin常用于氧化磷酸化解偶联、离子载体机制及β-catenin突变型肿瘤凋亡研究[4]。
体外实验中，用Nonactin（5μg/ml；处理 12-14h）处理BHK细胞可阻断NDV-HN和VSV-G糖蛋白的细胞表面表达，而不减少其总合成，导致VSV-G在细胞内积聚，抑制合胞体形成并降低病毒产量[5]。用Nonactin（0.12-0.5µM；72h）处理髓样甲状腺癌TT细胞可降低RET蛋白和mRNA水平，抑制pAKT/pmTOR信号通路，诱导G1期阻滞，下调cyclin D1/E、E2F1和BCL-2，增加γH2AX和cleaved PARP，并提升 caspase-3/7活性[6]。
在体内，Nonactin（100mg/kg/天；腹腔注射；4 天）在β-catenin突变型HCT 116异种移植小鼠中显著诱导肿瘤退缩和大量TUNEL阳性细胞凋亡，且未引起明显体重下降[7]。