Amlexanox reversibly inhibits cell migration and proliferation and inducesthe Src-dependent disassembly of actin stress fibers in vitro

Amlexanox binds S100A13 and inhibits the release of fibroblast growth facto r 1 (FGF1). Because members of the S100 gene family are known to be involve d with the function of the cytoskeleton, we examined the ability of amlexan ox to modify the cytoskeleton and report that amlexanox induces a dramatic reduction in the presence of actin stress fibers and the appearance of a ra ndom, non-oriented distribution of focal adhesion sites. Correspondingly, a mlexanox induces the complete and reversible non-apoptotic inhibition of ce ll migration and proliferation, and although amlexanox does not induce eith er the down-regulation of F-actin levels or the depolymerization of actin f ilaments, it does induce the tyrosine phosphorylation of cortactin, a Src s ubstrate known to regulate actin bundling. In addition, a dominant negative form of Src is able to partially rescue cells from the effect of amlexanox on both the actin cytoskeleton and cell migration. In contrast, the inhibi tion of cell proliferation by amlexanox correlates with the inhibition of c yclin D1 expression without interference of the receptor tyrosine kinase/mi togen-activated protein kinase signaling pathway. Last, the ability of amle xanox to inhibit FGF1 release is reversible and correlates with the restora tion of the actin cytoskeleton, suggesting a role for the actin cytoskeleto n in the FGF1 release pathway.