Nuclear permeable ruthenium(II) β-carboline complexes induce autophagy to antagonize mitochondrial-mediated apoptosis

J Med Chem. 2010 Nov 11;53(21):7613-24. doi: 10.1021/jm1009296.

Abstract

The role of autophagy in cancer development and response to cancer therapy has been a subject of debate. Here we demonstrate that a series of ruthenium(II) complexes containing a β-carboline alkaloid as ligand can simultaneously induce autophagy and apoptosis in tumor cells. These Ru(II) complexes are nuclear permeable and highly active against a panel of human cancer cell lines, with complex 3 displaying activities greater than those of cisplatin. The antiproliferative potentialities of 1-3 are in accordance with their relative lipophilicities, cell membrane penetration abilities, and in vitro DNA binding affinities. Complexes 1-3 trigger release of reactive oxygen species (ROS) and attenuation of ROS by scavengers reduced the sub-G1 population, suggesting ROS-dependent apoptosis. Inhibition of ROS generation also reduces autophagy, indicating that ROS triggers autophagy. Further studies show that suppression of autophagy using pharmacological inhibitors (3-methyladenine and chloroquine) enhances apoptotic cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Carbolines / chemical synthesis*
  • Carbolines / chemistry
  • Carbolines / pharmacology
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Cell Nucleus / metabolism*
  • Coordination Complexes / chemical synthesis*
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology
  • DNA / chemistry
  • Drug Screening Assays, Antitumor
  • Green Fluorescent Proteins / genetics
  • Humans
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / physiology*
  • Reactive Oxygen Species / metabolism
  • Ruthenium*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Carbolines
  • Coordination Complexes
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • Reactive Oxygen Species
  • Green Fluorescent Proteins
  • Ruthenium
  • DNA