A novel geranylgeranyl transferase inhibitor in combination with lovastatin inhibits proliferation and induces autophagy in STS-26T MPNST cells

J Pharmacol Exp Ther. 2010 Apr;333(1):23-33. doi: 10.1124/jpet.109.160192. Epub 2010 Jan 19.

Abstract

Prenylation inhibitors have gained increasing attention as potential therapeutics for cancer. Initial work focused on inhibitors of farnesylation, but more recently geranylgeranyl transferase inhibitors (GGTIs) have begun to be evaluated for their potential antitumor activity in vitro and in vivo. In this study, we have developed a nonpeptidomimetic GGTI, termed GGTI-2Z [(5-nitrofuran-2-yl)methyl-(2Z,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl 4-chlorobutyl(methyl)phosphoramidate], which in combination with lovastatin inhibits geranylgeranyl transferase I (GGTase I) and GGTase II/RabGGTase, without affecting farnesylation. The combination treatment results in a G(0)/G(1) arrest and synergistic inhibition of proliferation of cultured STS-26T malignant peripheral nerve sheath tumor cells. We also show that the antiproliferative activity of drugs in combination occurs in the context of autophagy. The combination treatment also induces autophagy in the MCF10.DCIS model of human breast ductal carcinoma in situ and in 1c1c7 murine hepatoma cells, where it also reduces proliferation. At the same time, there is no detectable toxicity in normal immortalized Schwann cells. These studies establish GGTI-2Z as a novel geranylgeranyl pyrophosphate derivative that may work through a new mechanism involving the induction of autophagy and, in combination with lovastatin, may serve as a valuable paradigm for developing more effective strategies in this class of antitumor therapeutics.

Publication types

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

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Autophagy*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Diterpenes / pharmacology*
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • G1 Phase / drug effects
  • GTP Phosphohydrolases / metabolism
  • Humans
  • Lovastatin / pharmacology*
  • Mice
  • Organophosphorus Compounds / pharmacology*
  • Protein Prenylation
  • Resting Phase, Cell Cycle / drug effects
  • Schwann Cells / cytology
  • Schwann Cells / drug effects
  • Transferases / antagonists & inhibitors*

Substances

  • ((5-nitrofuran-2-yl)methyl-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl 4-chlorobutyl(methyl)phosphoramidate)
  • Antineoplastic Agents
  • Diterpenes
  • Organophosphorus Compounds
  • Rab geranylgeranyl transferase beta-subunit
  • Lovastatin
  • Transferases
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • p21(ras) farnesyl-protein transferase
  • GTP Phosphohydrolases