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.
Footnotes
- Received August 7, 2009.
- Accepted January 15, 2010.
This work was supported by the Department of the Army [Grants DAMD17-03-1-0182, W81XWH-05-1-0193]; the National Institutes of Health [Grant R01-CA131990]; and the National Institutes of Health National Institutes of Environmental Health Sciences [Grant P30-ES06639] (Environmental Health Sciences Center Pilot Project). This project was aided by the Imaging and Cytometry Core Facilities at Wayne State University, which were supported by the National Institute of Environmental Health Sciences [Grant P30-ES06639] and the National Cancer Institute [Grant P30-CA22453]. J.W.W. was supported by the National Institutes of Health [Grant T32-ES012163]. Work at Purdue was supported in part by the National Institutes of Health [Grants R01-CA78819, P30-CA23168].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.160192.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
-
ABBREVIATIONS:
- GGTI
- geranylgeranyl transferase inhibitor
- GGTI-2Z (compound 7)
- (5-nitrofuran-2-yl)methyl-(2Z,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl 4-chlorobutyl(methyl)phosphoramidate
- GGPP
- geranylgeranyl pyrophosphate
- GGMP
- geranylgeranyl monophosphate
- FTase
- farnesyl transferase
- RabGGTase
- Rab geranylgeranyl transferase
- FTI
- farnesyl transferase inhibitor
- GGTase
- geranylgeranyl transferase
- MPNST
- malignant peripheral nerve sheath tumor
- iSC
- immortalized Schwann cells
- NF1
- neurofibromatosis type I
- GI50
- concentration of drug for 50% inhibition of growth
- compound 1
- (6E,10E)-ethyl 7,11,16-trimethyl-3-oxohexadeca-6E,10E,14-trienoate
- compound 2
- (2E,6E,10E)-ethyl 7,11,15-trimethyl-3-(trifluoromethylsulfonyloxy)hexadeca-2,6,10,14-tetraenoate
- compound 3
- (2Z,6E,10E)-ethyl 3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenoate
- compound 4
- (2Z,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraen-1-ol (2Z-geranylgeraniol)
- compound 5
- 4-chlorobutyl(methyl)phosphoramidic dichloride
- compound 6
- (5-nitrofuran-2-yl)methyl 4-chlorobutyl(methyl)phosphoramidochloridate
- 2Z-GGMP (compound 8)
- 2Z geranylgeranyl monophosphate
- 2Z-GGPP (compound 9)
- 2Z-geranylgeranyl pyrophosphate
- DMSO
- dimethyl sulfoxide
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- DMF
- dimethylformamide
- THF
- tetrahydrofuran
- GFP
- green fluorescent protein
- HEK
- human embryonic kidney
- E64D
- l-3-trans-carboxyrane2
- LC3
- microtubule-associated protein-1 light chain 3
- LAMP-2
- lysosomal-associated membrane protein 2
- TEA
- triethylamine.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|