Restraining Cancer Cells by Dual Metabolic Inhibition with a Mitochondrion-Targeted Platinum(II) Complex

Angew Chem Int Ed Engl. 2019 Mar 26;58(14):4638-4643. doi: 10.1002/anie.201900387. Epub 2019 Feb 27.

Abstract

Cancer cells usually adapt metabolic phenotypes to chemotherapeutics. A defensive strategy against this flexibility is to modulate signaling pathways relevant to cancer bioenergetics. A triphenylphosphonium-modified terpyridine platinum(II) complex (TTP) was designed to inhibit thioredoxin reductase (TrxR) and multiple metabolisms of cancer cells. TTP exhibited enhanced cytotoxicity against cisplatin-insensitive human ovarian cancer cells in a caspase-3-independent manner and showed preferential inhibition to mitochondrial TrxR. The morphology and function of mitochondria were severely damaged, and the levels of mitochondrial and cellular reactive oxygen species were decreased. As a result, TTP exerted strong inhibition to both mitochondrial and glycolytic bioenergetics, thus inducing cancer cells to enter a hypometabolic state.

Keywords: antitumor agents; metabolism; mitochondria; platinum; thioredoxin reductase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Cisplatin / chemistry
  • Cisplatin / pharmacology*
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Microscopy, Fluorescence
  • Models, Molecular
  • Optical Imaging
  • Oxaliplatin / chemistry
  • Oxaliplatin / pharmacology*
  • Thioredoxin-Disulfide Reductase / antagonists & inhibitors*
  • Thioredoxin-Disulfide Reductase / metabolism

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Oxaliplatin
  • Thioredoxin-Disulfide Reductase
  • Cisplatin