Mitochondria-Accumulating Rhenium(I) Tricarbonyl Complexes Induce Cell Death via Irreversible Oxidative Stress and Glutathione Metabolism Disturbance

ACS Appl Mater Interfaces. 2019 Apr 10;11(14):13123-13133. doi: 10.1021/acsami.9b01057. Epub 2019 Mar 27.

Abstract

Mitochondria play a critical role in tumorigenesis. Targeting mitochondria and disturbing related events have been emerging as a promising way for chemotherapy. In this work, two binuclear rhenium(I) tricarbonyl complexes of the general formula [Re2(CO)6(dip)2L](PF6)2 (dip = 4,7-diphenyl-1,10-phenanthroline; L = 4,4'-azopyridine (ReN) or 4,4'-dithiodipyridine (ReS)) were synthesized and characterized. ReN and ReS can react with glutathione (GSH). They exhibit good in vitro anticancer activity against cancer cell lines screened. Besides, they can target mitochondria, cause oxidative stress, and disturb GSH metabolism. Both ReN and ReS can induce necroptosis and caspase-dependent apoptosis simultaneously. We also demonstrate that ReN and ReS can inhibit tumor growth in nude mice bearing carcinoma xenografts. Our study shows the potential of Re(I) complexes as chemotherapeutic agents to kill cancer cells via a mitochondria-to-cellular redox strategy.

Keywords: apoptosis; glutathione metabolism; mitochondrial dysfunction; necroptosis; oxidative stress; rhenium(I) complexes.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Apoptosis / drug effects
  • Carcinogenesis / drug effects*
  • Carcinoma / drug therapy*
  • Carcinoma / pathology
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Coordination Complexes / administration & dosage
  • Coordination Complexes / chemistry
  • Glutathione / antagonists & inhibitors
  • Glutathione / metabolism
  • Humans
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Oxidative Stress / drug effects
  • Reactive Oxygen Species / chemistry
  • Rhenium / administration & dosage*
  • Rhenium / chemistry
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Reactive Oxygen Species
  • Rhenium
  • Glutathione