Enhanced Sensitivity of G1 Arrested Human Cancer Cells Suggests a Novel Therapeutic Strategy Using a Combination of Simvastatin and TRAIL

Cell Cycle. 2002 Jan;1(1):82-9.

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cells over normal cells. To study the relationship between cell cycle progression and TRAIL-induced apoptosis, SW480 colon cancer and H460 lung cancer cell lines were examined for their sensitivity to TRAIL after arrest in different cell cycle phases. Cells were synchronized in G0/G1, S, and G2/M phase by serum starvation, aphidicolin, or nocodazole treatment, respectively. We found that arrest of cells in G0/G1 phase confers significantly higher susceptibility to TRAIL-induced apoptosis as compared to cells in late G1, S, or G2/M phase. To determine if cell cycle phase could be harnessed for therapeutic gain in the presence of TRAIL, we used the HMG-CoA reductase inhibitor, Simvastatin and lovastatin, to enrich a cancer cell population in G0/G1. Both simvastatin and lovastatin significantly augmented TRAIL-induced apoptosis in tumor cells, but not in normal keratinocytes. The results indicate that TRAIL, in combination with a HMG-CoA reductase inhibitor, may have therapeutic potential in the treatment of human cancer.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Caspase 9
  • Caspases / metabolism
  • Cell Cycle
  • Cell Division
  • Cells, Cultured
  • Cysteine Proteinase Inhibitors / pharmacology
  • Drug Therapy, Combination
  • G1 Phase
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Lovastatin / pharmacology
  • Membrane Glycoproteins / pharmacology*
  • Oligopeptides / pharmacology
  • Poly(ADP-ribose) Polymerases / metabolism
  • Resting Phase, Cell Cycle
  • Simvastatin / pharmacology*
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Cysteine Proteinase Inhibitors
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Membrane Glycoproteins
  • Oligopeptides
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone
  • Lovastatin
  • Simvastatin
  • Poly(ADP-ribose) Polymerases
  • CASP9 protein, human
  • Caspase 9
  • Caspases