3-Methyladenine is a classic autophagy inhibitor. It inhibits phosphatidylinositol 3-kinase (PI3K), which is located upstream of the IGF/PI3K/mTOR/ULK pathway.[1] 3-Methyladenine is capable to induce a consistent and abrupt decrease in cell viability across a series of ontologically unrelated human cell lines. In addition, 3-Methyladenine-induced cytotoxicity was not driven by the inhibition of the AKT/mTOR axis.[2]
In vitro study indicated that the inhibition of autophagy by 3-Methyladenine abolished uric acid-induced differentiation of renal fibroblasts to myofibroblasts and activation of transforming growth factor-β1 (TGF-β1), epidermal growth factor receptor (EGFR), and Wnt signaling pathways in cultured renal interstitial fibroblasts. Moreover, 3-Methyladenine was effective in attenuating renal deposition of extracellular matrix (ECM) proteins and expression of α-smooth muscle actin (α-SMA) and reducing renal epithelial cells arrested at the G2/M phase of cell cycle.[3]
In vivo study demonstrated that the administration of 3-Methyladenine inhibited Wnt/β-catenin and Notch/Jagged-1 signaling pathways as well as suppresses EGFR/ERK1/2 signaling pathway. Furthermore, 3-MA treatment remarkably inhibited the infiltration of macrophages and lymphocytes as well as release of multiple profibrogenic cytokines/chemokines in the injured kidney.[3]
References:
[1]. Yang F, et al. Rapamycin and 3-Methyladenine Influence the Apoptosis, Senescence, and Adipogenesis of Human Adipose-Derived Stem Cells by Promoting and Inhibiting Autophagy: An In Vitro and In Vivo Study. Aesthetic Plast Surg. 2021 Jun;45(3):1294-1309.
[2].Chicote J, et al. Cell Death Triggered by the Autophagy Inhibitory Drug 3-Methyladenine in Growing Conditions Proceeds With DNA Damage. Front Pharmacol. 2020 Oct 15;11:580343.
[3].Bao J, et al. Pharmacological inhibition of autophagy by 3-MA attenuates hyperuricemic nephropathy. Clin Sci (Lond). 2018 Nov 2;132(21):2299-2322.
3-甲基腺嘌呤是一种经典的自噬抑制剂。它抑制磷脂酰肌醇3-激酶（PI3K），该激酶位于IGF/PI3K/mTOR/ULK通路的上游[1]。 3-甲基腺嘌呤能够在一系列本体不相关的人类细胞系中诱导细胞存活率持续而突然地下降。此外， 3-甲基腺嘌呤引起的细胞毒性并非由AKT/mTOR轴的抑制驱动[2]。
实验室研究表明，使用3-甲基腺嘌呤可以抑制自噬作用，从而阻止尿酸诱导肾间质成纤维细胞向肌成纤维细胞分化和转化生长因子β1（TGF-β1）、表皮生长因子受体（EGFR）以及Wnt信号通路的激活。此外，3-甲基腺嘌呤还能有效减轻肾脏中胞外基质（ECM）蛋白沉积和α平滑肌动力蛋白（α-SMA）的表达，并降低停留在G2/M期的肾上皮细胞数量。
动物实验表明，给予3-甲基腺嘌呤可以抑制Wnt/β-catenin和Notch/Jagged-1信号通路，并且还能抑制EGFR/ERK1/2信号通路。此外，3-MA治疗显著抑制了肾损伤中巨噬细胞和淋巴细胞的浸润以及多种促纤维化的细胞因子/趋化因子的释放。