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- Title
Pifithrin-μ induces necroptosis through oxidative mitochondrial damage but accompanies epithelial–mesenchymal transition-like phenomenon in malignant mesothelioma cells under lactic acidosis.
- Authors
Lee, Yoon-Jin; Park, Kwan-Sik; Heo, Su-Hak; Nam, Hae-Seon; Cho, Moon-Kyun; Lee, Sang-Han
- Abstract
Heat shock protein 70 (HSP70), a chaperone protein associated with tumorigenesis and chemoresistance, has attracted significant attention as a potential therapeutic target for the development of anticancer drugs. Here, the effects of pifithrin-μ, an effective dual inhibitor of HSP70 and p53, on anticancer activities and epithelial–mesenchymal transition (EMT) were investigated in malignant mesothelioma (MM) cells. MSTO-211HAcT cells, pre-incubated in a medium containing lactic acid, showed more potent resistance to cisplatin and gemcitabine, compared with their acid-sensitive parental MSTO-211H cells. Pifithrin-μ treatment induced both apoptosis and necroptosis, which were accompanied by an EMT-like phenomenon, as evidenced by an elongated cell morphology, decreased levels of epithelial cell markers including E-cadherin, claudin-1, and β-catenin, increased levels of mesenchymal markers including Snail, Slug, and vimentin, and increased cell migratory property. Moreover, pifithrin-μ increased intracellular ROS levels, which is associated with mitochondrial dysfunction and decreased cellular ATP content. A series of changes caused by pifithrin-μ treatment were effectively restored by lowering the ROS level through pretreatment with N-acetylcysteine. Collectively, our results suggest that pifithrin-μ may promote the metastatic behavior of surviving cells by triggering the EMT, despite its effective cell-killing action against MM cells, possibly linked to oxidative mitochondrial dysfunction and ATP depletion.
- Publication
Archives of Pharmacal Research, 2019, Vol 42, Issue 10, p890
- ISSN
0253-6269
- Publication type
Article
- DOI
10.1007/s12272-019-01181-6