Discovery and Identification of Small Molecules as Methuosis Inducers with in Vivo Antitumor Activities

Methuosis is a novel nonapoptotic mode of cell death characterized by vacuole accumulation in the cytoplasm. In this article, we describe a series of azaindole-based compounds that cause vacuolization in MDA-MB-231 cells. The most potent vacuole inducer, compound 13 (compound 13), displayed differential cytotoxicities against a broad panel of cancer cell lines, such as MDA-MB-231, A375, HCT116, and MCF-7, but it did not inhibit the growth of the nontumorigenic epithelial cell line MCF-10A. A mechanism study confirmed that the cell death was caused by inducing methuosis. Furthermore, compound 13 exhibited substantial pharmacological efficacy in the suppression of tumor growth in a xenograft mouse model of MDA-MB-231 cells without apparent side effects, which makes this compound the first example of a methuosis inducer with potent in vivo efficacy. These results demonstrate that methuosis inducers might serve as novel therapeutics for the treatment of cancer.泡亡（Methuosis）是一种新型非凋亡性细胞死亡模式，其特征为细胞质内空泡蓄积。本文报道了一系列基于氮杂吲哚（azaindole）的化合物，可诱导MDA-MB-231细胞发生空泡化。其中活性最强的空泡诱导剂——化合物13，对MDA-MB-231、A375、HCT116及MCF-7等广谱癌细胞系展现出差异化细胞毒性，但并未抑制非致瘤性上皮细胞系MCF-10A的生长。机制研究证实，该细胞死亡是通过诱导泡亡发生所致。此外，化合物13在MDA-MB-231细胞异种移植小鼠模型中展现出显著的抗肿瘤生长药理活性，且未观察到明显毒副作用，使其成为首款具备强效体内活性的泡亡诱导剂。上述结果表明，泡亡诱导剂有望成为新型癌症治疗药物。