Truncated Actin-Targeting Macrolide Derivative Blocks Cancer Cell Motility and Invasion of Extracellular Matrix

Abstract

Cancer metastasis is a complex process involving highly motile tumor cells that breach tissue barriers, enter the bloodstream and lymphatic system, and disseminate throughout the body as circulating tumor cells. The primary cellular mechanism contributing to these critical events is the reorganization of the actin cytoskeleton. Mycalolide B (MycB) is an actintargeting marine macrolide that can suppress proliferation, migration, and invasion of breast and ovarian cancer cells at low nanomolar doses. Through structure−activity relationship studies focused on the actin-binding tail region (C24−C35) of MycB, we identified a potent truncated derivative that inhibits polymerization of G-actin and severs F-actin by binding to actin's barbed end cleft. Biological analyses of this miniature MycB derivative demonstrate that it causes a rapid collapse of the actin cytoskeleton in ovarian cancer cells and impairs cancer cell motility and invasion of the extracellular matrix (ECM) by inhibiting invadopodia-mediated ECM degradation. These studies provide essential proof-of-principle for developing actin-targeting therapeutic agents to block cancer metastasis and establish a synthetically tractable barbed end-binding pharmacophore that can be further improved by adding targeting groups for precision drug design.

Actin-Associated Proteins and Small Molecules Targeting the Actin Cytoskeleton

“…Kabiramide C and Mycalolide B belong to the trisoxazole family that mimics the binding of actin-capping proteins to actin in order to sever F-actin and cap the barbed end [112,113] (Figure 4). The macrolide derivative blocks cancer cell motility and invasion [103]. The reidispongiolide/sphinxolide family also binds to a hydrophobic cleft between actin subdomains 1 and 3 to sever F-actin and cap the barbed end [113].…”

A Ruthenium(II) Polypyridyl Complex Disrupts Actin Cytoskeleton Assembly and Blocks Cytokinesis

“…[43] Although actin is not commonly regarded as a therapeutic target, [7] G-actin polymerisation inhibitors that target cytoskeletal organisation exhibit considerable antiproliferative and anti-metastatic activity. [44,45] Within this context, in addition to blocking cytokinesis, RuRuPhen also inhibits cell spreading and motility (Figure S6). Together, these effects impacted cell viability of three cancer cell lines with potencies comparable to cisplatin but with a significantly reduced effect on a non-cancer cell line (Figure S7 and Table S1).…”

“…Although actin is not commonly regarded as a therapeutic target, [7] G‐actin polymerisation inhibitors that target cytoskeletal organisation exhibit considerable anti‐proliferative and anti‐metastatic activity [44, 45] . Within this context, in addition to blocking cytokinesis, RuRuPhen also inhibits cell spreading and motility (Figure S6).…”

Cytoskeleton Protein BmACT1 Is Potential for the Autophagic Function and Nuclear Localization of BmAtg4b in Bombyx mori

“…In contrast, actin isoforms have different structures and thus function differently [ 18 ]. In breast and ovarian cancer cells, the actin skeleton facilitates the motility of cancer cells, which provides a basis for developing therapeutic agents to block cancer metastasis by targeting actin [ 19 ]. Besides, the movement of bacterial pathogens such as Listeria and Shigella is realized by the polymerization and movement of actin [ 20 ].…”