Econazole, a potent broad-spectrum
antifungal agent and a Ca2+ channel antagonist, induces cytotoxicity in
leukemia cells and is used for the
treatment of
skin infections. However, little is known about its cytotoxic effects on solid
tumor cells. Here, we investigated the molecular mechanism underlying
econazole-induced
toxicity in vitro and evaluated its regulatory effect on the
metastasis of
gastric cancer cells. Using the
gastric cancer cell lines AGS and SNU1 expressing wild-type p53 we demonstrated that
econazole could significantly reduce
cell viability and colony-forming (
tumorigenesis)
ability.
Econazole induced G0/
G1 phase arrest, promoted
apoptosis, and effectively blocked proliferation- and
survival-related
signal transduction pathways in
gastric cancer cells. In addition,
econazole inhibited the
secretion of
matrix metalloproteinase- 2 (
MMP-2) and
MMP-9, which degrade the
extracellular matrix and
basement membrane.
Econazole also effectively inhibited the
metastasis of
gastric cancer cells, as confirmed from
cell invasion and
wound healing assays. The
protein level of p53 was significantly elevated after
econazole treatment of AGS and SNU1
cells. However,
apoptosis was blocked in
econazole-treated
cells exposed to a p53-specific small-interfering
RNA to eliminate p53 expression. These results provide evidence that
econazole could be repurposed to induce
gastric cancer cell death and inhibit
cancer invasion.