Econazole Induces p53-Dependent Apoptosis and Decreases Metastasis Ability in Gastric Cancer Cells

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