Discovery of small-molecule enhancers of reactive oxygen species that are nontoxic or cause genotype-selective cell death

ACS Chem Biol. 2013 May 17;8(5):923-9. doi: 10.1021/cb300653v. Epub 2013 Mar 25.

Abstract

Elevation of reactive oxygen species (ROS) levels has been observed in many cancer cells relative to nontransformed cells, and recent reports have suggested that small-molecule enhancers of ROS may selectively kill cancer cells in various in vitro and in vivo models. We used a high-throughput screening approach to identify several hundred small-molecule enhancers of ROS in a human osteosarcoma cell line. A minority of these compounds diminished the viability of cancer cell lines, indicating that ROS elevation by small molecules is insufficient to induce death of cancer cell lines. Three chemical probes (BRD5459, BRD56491, BRD9092) are highlighted that most strongly elevate markers of oxidative stress without causing cell death and may be of use in a variety of cellular settings. For example, combining nontoxic ROS-enhancing probes with nontoxic doses of L-buthionine sulfoximine, an inhibitor of glutathione synthesis previously studied in cancer patients, led to potent cell death in more than 20 cases, suggesting that even nontoxic ROS-enhancing treatments may warrant exploration in combination strategies. Additionally, a few ROS-enhancing compounds that contain sites of electrophilicity, including piperlongumine, show selective toxicity for transformed cells over nontransformed cells in an engineered cell-line model of tumorigenesis. These studies suggest that cancer cell lines are more resilient to chemically induced increases in ROS levels than previously thought and highlight electrophilicity as a property that may be more closely associated with cancer-selective cell death than ROS elevation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / pathology
  • Buthionine Sulfoximine / pharmacology
  • Cell Death / drug effects
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dioxolanes / pharmacology
  • Drug Screening Assays, Antitumor / methods
  • High-Throughput Screening Assays / methods*
  • Humans
  • Molecular Probes / chemistry
  • Molecular Probes / metabolism*
  • Molecular Probes / pharmacology*
  • Osteosarcoma / drug therapy
  • Osteosarcoma / pathology
  • Oxidative Stress / drug effects
  • Reactive Oxygen Species / metabolism*
  • Small Molecule Libraries / pharmacology

Substances

  • Antineoplastic Agents
  • Dioxolanes
  • Molecular Probes
  • Reactive Oxygen Species
  • Small Molecule Libraries
  • Buthionine Sulfoximine
  • piperlonguminine