An Ursolic Acid Derived Small Molecule Triggers Cancer Cell Death through Hyperstimulation of Macropinocytosis,Journal of Medicinal Chemistry

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An Ursolic Acid Derived Small Molecule Triggers Cancer Cell Death through Hyperstimulation of Macropinocytosis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-19 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00592
Lin Sun ₁ , Bin Li ₁ , Xiaohui Su ₁ , Ge Chen ₂ , Yaqin Li ₁ , Linqian Yu ₁ , Li Li ₃ , Wanguo Wei _{1,

2}

Affiliation

Macropinocytosis is a transient endocytosis that internalizes extracellular fluid and particles into vacuoles. Recent studies suggest that hyperstimulation of macropinocytosis can induce a novel nonapoptotic cell death, methuosis. In this report, we describe the identification of an ursolic acid derived small molecule (compound 17), which induces cancer cell death through hyperstimulation of macropinocytosis. 17 causes the accumulation of vacuoles derived from macropinosomes based on transmission electron microscopy, time-lapse microscopy, and labeling with extracellular fluid phase tracers. The vacuoles induced by 17 separate from other cytoplasmic compartments but acquire some characteristics of late endosomes and lysosomes. Inhibiting hyperstimulation of macropinocytosis with the specific inhibitor amiloride blocks cell death, implicating that 17 leads to cell death via macropinocytosis, which is coincident with methuosis. Our results uncovered a novel cell death pathway involved in the activity of 17, which may provide a basis for further development of natural-product-derived scaffolds for drugs that trigger cancer cell death by methuosis.

中文翻译：

熊果酸衍生的小分子通过巨胞吞作用的过度刺激触发癌细胞死亡

巨胞饮作用是一种短暂的内吞作用，可将细胞外液和颗粒内在化为液泡。最近的研究表明，巨胞吞作用的过度刺激可以诱导新的非凋亡性细胞死亡，变态。在此报告中，我们描述了熊果酸衍生的小分子（化合物17）的鉴定，该分子通过过度刺激巨噬细胞增多而诱导癌细胞死亡。基于透射电子显微镜，延时显微镜和用细胞外液示踪剂标记，图17引起源自大体脂质体的液泡的积累。17引起的空泡与其他细胞质区室分开，但具有晚期内体和溶酶体的某些特征。用特异的抑制剂阿米洛利抑制巨噬细胞增多过度刺激可阻止细胞死亡，这暗示着17通过巨噬细胞增多导致细胞死亡，这与变态反应同时发生。我们的研究结果揭示了涉及17活性的新型细胞死亡途径，这可能为进一步开发天然产物衍生的支架提供基础，该支架用于药物通过变态作用触发癌细胞死亡。

更新日期：2017-07-20

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