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

Abstract

Econazole, a potent broad-spectrum antifungal agent and a Ca 2+ 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.

Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells

“…The current data are consistent with Dong and his colleagues' study that showed that econazole (Imidazole derivative) induces apoptosis in lung cancer cells through the PI3K/AKT signaling pathways. Hence, their data represented that p-AKT and p-PI3K expression levels were downregulated entirely by econazole [46]. This in agreement with a previous study that reported PI3K inhibitors combinations with doxorubicin exhibit better efficacy than monotherapy due to their strong synergistic antiproliferative effect of those combinations, via inducing PI3K/AKT signaling blockage, which in turn led to activate caspase-3/7 and caspase-9 and changed the expression of several apoptosis-related gene expression [47].…”

CAMSAP1 Mutation Correlates With Improved Prognosis in Small Cell Lung Cancer Patients Treated With Platinum-Based Chemotherapy

“…Anisomycin can inhibit angiogenesis, proliferation and invasion of tumor cells by blocking the PI3K/Akt pathway ( Ushijima et al, 2021 )and Notch1 pathway ( Ye et al, 2019 ). Econazole induces cell apoptosis and inhibits cancer invasion through the elevated protein level of p53 ( Choi et al, 2020 ). Imatinib reduces the phosphorylation of the PDGFRα/Akt axis, suppressing tumor cell growth and migration ( Nayeem et al, 2021 ).…”

Loss of EMP2 Inhibits Melanogenesis of MNT1 Melanoma Cells via Regulation of TRP-2

“…Invasion assays were performed using transwells that were coated with Matrigel (0.5 μg/mL) (Neuro Probe Inc., Gaithersburg, MD) following a previous report ( Choi et al ., 2020 ). Coat Matrigel (10 μL/well) in the transwell insert, overnight at room temperature.…”