CRM646-A, a Fungal Metabolite, Induces Nucleus Condensation by Increasing Ca2+ Levels in Rat 3Y1 Fibroblast Cells

Abstract

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 Ca 2 + 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 Ca 2 + ionophore-like agent with a distinctly different chemical structure from that of previously reported Ca 2 + ionophores. These results indicate that CRM646-A has the potential to be used as a new and effective antimetastatic drug.

Fungal Depsides—Naturally Inspiring Molecules: Biosynthesis, Structural Characterization, and Biological Activities

“…They also caused the dose-dependent inhibition of heparinase, with IC 50 values of 3 and 10 µM, respectively, in comparison to suramin (IC 50 value of 5 µM) [43,44]. Asami et al established that CRM646-A (36) induced the inhibition of cells' invasion, migration, and growth in tumor cells, due to its induction of nucleus condensation, plasma membrane disruption, and morphological changes in result to the increase in Ca 2+ levels; thus, it could potentially be used as an effective anti-metastatic agent [45]. Compounds 45 and 46 in the MTT assay showed an antitumor effect against A549 and MAD-MB-435, with IC 50 values of 16.82 and 37.01 µM, and 20.75 and 37.73 µM, respectively, compared with epirubicin (IC 50 0.26 and 5.60 µM, respectively); however, 11 did not exhibit obvious activity [46].…”