Gemifloxacin (
GMF) is a
fluoroquinolone antibiotic that inhibits
bacterial DNA gyrase and
topoisomerase IV. The aim of this study was to investigate the anti-metastatic activities of
GMF and its possible mechanisms of action, with a special focus on the induction of mesenchymal-epithelial transition (MET). The human breast
adenocarcinoma cell lines MDA-MB-231 and MDA-MB-453 were used to assess the anti-metastatic activity of
GMF on cell migration and invasion and in scratch wound-healing assays. The effects of
GMF on the MET and its regulatory nuclear factor κB (NF-κB)/Snail pathway were assessed. The in vivo anti-metastatic effect of
GMF was also evaluated in an animal model. This study demonstrated that
GMF inhibited the migration and invasion of MDA-MB-231 and MDA-MB-453 cells and induced the MET.
GMF suppressed the activation of NF-κB, as well as the cell migration and invasion induced by
tumor necrosis factor α (TNF-α).
GMF was shown to inhibit the phosphorylation of the inhibitor of κB (IκB) and the translocation of NF-κB/Snail in both
cancer cell lines. This study showed that the
Raf kinase inhibitor protein (RKIP), an inhibitor of IκB
kinase, is upregulated after
GMF treatment. Inhibition of RKIP by
small hairpin RNA transfection significantly decreased the inhibitory effect of
GMF on the NF-κB/Snail pathway and also inhibited cell migration and invasion. Overexpression of Snail suppressed
GMF-mediated
metastasis inhibition and
E-cadherin upregulation. An animal model revealed that
GMF effectively inhibits
lipopolysaccharide-mediated
metastasis in mice. This study has demonstrated that
GMF might be a novel
anticancer agent for the prevention and treatment of
metastasis in
breast cancer.
KEY MESSAGES:
GMF inhibits the migration and invasion of human breast
adenocarcinoma cells.
GMF induces MET by reducing NF-κB and Snail activation and by increasing RKIP levels.
GMF has potential clinical implication as an anti-metastatic agent for
breast cancer.