LDHA Suppression Altering Metabolism Inhibits Tumor Progress by an Organic Arsenical

Int J Mol Sci. 2019 Dec 11;20(24):6239. doi: 10.3390/ijms20246239.

Abstract

Based on the potential therapeutic value in targeting metabolism for the treatment of cancer, an organic arsenical PDT-BIPA was fabricated, which exerted selective anti-cancer activity in vitro and in vivo via targeting lactate dehydrogenase A (LDHA) to remodel the metabolic pathway. In details, the precursor PDT-BIPA directly inhibited the function of LDHA and converted the glycolysis to oxidative phosphorylation causing ROS burst and mitochondrial dysfunction. PDT-BIPA also altered several gene expression, such as HIF-1α and C-myc, to support the metabolic remodeling. All these changes lead to caspase family-dependent cell apoptosis in vivo and in vitro without obvious side effect. Our results provided this organic arsenical precursor as a promising anticancer candidate and suggested metabolism as a target for cancer therapies.

Keywords: ROS; apoptosis; lactate dehydrogenase A; metabolism; mitochondria; organic arsenicals.

MeSH terms

  • Animals
  • Arsenicals / chemical synthesis
  • Arsenicals / chemistry
  • Arsenicals / pharmacology*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Respiration / drug effects
  • Disease Progression*
  • Female
  • Glutathione / metabolism
  • Humans
  • Ki-67 Antigen / metabolism
  • Lactate Dehydrogenase 5 / antagonists & inhibitors
  • Lactate Dehydrogenase 5 / metabolism*
  • Mice, Nude
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Organic Chemicals / chemical synthesis
  • Organic Chemicals / chemistry
  • Organic Chemicals / pharmacology*
  • Oxygen Consumption / drug effects
  • Pyruvate Dehydrogenase Complex / metabolism
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism
  • Thioredoxins / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Arsenicals
  • Ki-67 Antigen
  • Organic Chemicals
  • Pyruvate Dehydrogenase Complex
  • Reactive Oxygen Species
  • Thioredoxins
  • Lactate Dehydrogenase 5
  • Glutathione