We previously identified a new heparinase inhibitor fungal metabolite, named CRM646-A, which showed inhibition of heparinase and telomerase activities in an in vitro enzyme assay and antimetastatic activity in a cell-based assay. In this study, we elucidated the mechanism by which CRM646-A rapidly induced nucleus condensation, plasma membrane disruption and morphological changes by increasing intracellular Ca²⁺ levels. Furthermore, PD98059, a mitogen-activated protein kinase (MEK) inhibitor, inhibited CRM646-A-induced nucleus condensation through ERK1/2 activation in rat 3Y1 fibroblast cells. We identified CRM646-A as a Ca²⁺ ionophore-like agent with a distinctly different chemical structure from that of previously reported Ca²⁺ ionophores. These results indicate that CRM646-A has the potential to be used as a new and effective antimetastatic drug.

中文翻译：

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CRM646-A 是一种真菌代谢物，通过增加大鼠 3Y1 成纤维细胞中的 Ca2+ 水平来诱导细胞核凝聚。


我们之前鉴定了一种新的肝素酶抑制剂真菌代谢物，名为 CRM646-A，它在体外酶测定中显示出对肝素酶和端粒酶活性的抑制作用，在基于细胞的测定中显示出抗转移活性。在本研究中，我们阐明了CRM646-A通过增加细胞内Ca ²⁺水平快速诱导细胞核浓缩、质膜破坏和形态变化的机制。此外，PD98059 是一种丝裂原激活蛋白激酶 (MEK) 抑制剂，可通过大鼠 3Y1 成纤维细胞中的 ERK1/2 激活来抑制 CRM646-A 诱导的细胞核浓缩。我们将 CRM646-A 鉴定为一种类 Ca ²⁺离子载体试剂，其化学结构与之前报道的 Ca ²⁺离子载体明显不同。这些结果表明CRM646-A有潜力用作新型有效的抗转移药物。