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Pifithrin-μ Induces Necroptosis Through Oxidative Mitochondrial Damage but Accompanies Epithelial-Mesenchymal Transition-Like Phenomenon in Malignant Mesothelioma Cells Under Lactic Acidosis

Pifithrin-μ Induces Necroptosis Through Oxidative Mitochondrial Damage but Accompanies Epithelial-Mesenchymal Transition-Like Phenomenon in Malignant Mesothelioma Cells Under Lactic Acidosis

Yoon-Jin Lee, Kwan-Sik Park, Su-Hak Heo, Hae-Seon Nam, Moon-Kyun Cho, Sang-Han Lee

Arch Pharm Res. 2019 Oct;42(10):890-901.

PMID: 31428976

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP64984312-A	Pifithrin-μ		64984-31-2	Price

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