Choi Eun Kyoung, Park Eun Jung, Phan Tien Thuy, Kim Hea Dong, Hoe Kwang-Lae, Kim Dong-Uk
Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
Department of Functional Genomics, KRIBB School of Biosciences, University of Science and Technology (UST), Daejeon 34113, Republic of Korea.
Biomol Ther (Seoul). 2020 Jul 1;28(4):370-379. doi: 10.4062/biomolther.2019.201.
Econazole, a potent broad-spectrum antifungal agent and a Ca 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 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.
益康唑是一种强效广谱抗真菌剂和钙通道拮抗剂，可诱导白血病细胞产生细胞毒性，用于治疗皮肤感染。然而，其对实体瘤细胞的细胞毒性作用知之甚少。在此，我们研究了益康唑诱导毒性的分子机制，并评估了其对胃癌细胞转移的调节作用。使用表达野生型p53的胃癌细胞系AGS和SNU1，我们证明益康唑可显著降低细胞活力和集落形成（肿瘤发生）能力。益康唑诱导G0/G1期阻滞，促进细胞凋亡，并有效阻断胃癌细胞中与增殖和存活相关的信号转导途径。此外，益康唑抑制基质金属蛋白酶-2（MMP-2）和MMP-9的分泌，这两种酶可降解细胞外基质和基底膜。从细胞侵袭和伤口愈合试验证实，益康唑还能有效抑制胃癌细胞的转移。用益康唑处理AGS和SNU1细胞后，p53的蛋白水平显著升高。然而，在暴露于p53特异性小干扰RNA以消除p53表达的经益康唑处理的细胞中，细胞凋亡被阻断。这些结果提供了证据，表明益康唑可被重新用于诱导胃癌细胞死亡并抑制癌症侵袭。
