Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2019.201
Econazole Induces p53-Dependent Apoptosis and Decreases Metastasis Ability in Gastric Cancer Cells
Eun Kyoung Choi1, Eun Jung Park1, Tien Thuy Phan1,2, Hea Dong Kim1, Kwang-Lae Hoe3,* and Dong-Uk Kim1,*
1Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 34141,
2Department of Functional Genomics, KRIBB School of Biosciences, University of Science and Technology (UST), Daejeon 34113,
3Department of New Drug Development, Chungnam National University, Daejeon 34134, Republic of Korea
E-mail: kwanghoe@cnu.ac.kr (Hoe KL), kimdongu@kribb.re.kr (Kim DU)
Tel: +82-42-821-8627 (Hoe KL), +82-42-860-4159 (Kim DU)
Fax: +82-42-821-8927 (Hoe KL), +82-42-860-4149 (Kim DU)
Received: December 2, 2019; Revised: December 27, 2019; Accepted: December 28, 2019; Published online: March 25, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Econazole, a potent broad-spectrum antifungal agent and a Ca2+ 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 in vitro 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.
Keywords: Apoptosis, Econazole, Gastric cancer, Invasion, Migration, p53


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