Pifithrin-μ induces necroptosis through oxidative mitochondrial damage but accompanies epithelial-mesenchymal transition-like phenomenon in malignant mesothelioma cells under lactic acidosis

Arch Pharm Res. 2019 Oct;42(10):890-901. doi: 10.1007/s12272-019-01181-6. Epub 2019 Aug 19.

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.

Keywords: Epithelial–mesenchymal transition; Heat shock protein 70; Malignant mesothelioma; Necroptosis; Pifithrin-μ; p53.

MeSH terms

  • Acidosis, Lactic / complications*
  • Acidosis, Lactic / metabolism
  • Acidosis, Lactic / pathology
  • Apoptosis / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Epithelial-Mesenchymal Transition / drug effects*
  • Humans
  • Hydrogen-Ion Concentration
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • Membrane Potential, Mitochondrial / drug effects
  • Mesothelioma / drug therapy
  • Mesothelioma / metabolism*
  • Mesothelioma / pathology*
  • Mesothelioma, Malignant
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Necroptosis / drug effects*
  • Oxidative Stress / drug effects*
  • Structure-Activity Relationship
  • Sulfonamides / pharmacology*
  • Tumor Cells, Cultured

Substances

  • 2-phenylacetylenesulfonamide
  • Sulfonamides