A Novel Geranylgeranyl Transferase Inhibitor in Combination with Lovastatin Inhibits Proliferation and Induces Autophagy in STS-26T MPNST Cells
- 19 January 2010
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Journal of Pharmacology and Experimental Therapeutics
- Vol. 333 (1), 23-33
- https://doi.org/10.1124/jpet.109.160192
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 G0/G1 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.Keywords
This publication has 42 references indexed in Scilit:
- Regulation of Rac1 by Simvastatin in Endothelial CellsPublished by Elsevier BV ,2009
- Blockade of Protein Geranylgeranylation Inhibits Cdk2-Dependent p27Kip1 Phosphorylation on Thr187 and Accumulates p27Kip1 in the Nucleus: Implications for Breast Cancer TherapyMolecular and Cellular Biology, 2009
- Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington diseaseJournal of Cell Science, 2008
- Synthesis and evaluation of 3- and 7-substituted geranylgeranyl pyrophosphate analogsBioorganic & Medicinal Chemistry Letters, 2008
- Towards Complete Sets of Farnesylated and Geranylgeranylated ProteinsPLoS Computational Biology, 2007
- Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthaseBiochemical and Biophysical Research Communications, 2006
- Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoterOncogene, 2006
- Peptide Specificity of Protein Prenyltransferases Is Determined Mainly by Reactivity Rather than Binding AffinityBiochemistry, 2005
- Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitorsCancer Cell, 2005
- The RAB25 small GTPase determines aggressiveness of ovarian and breast cancersNature Medicine, 2004