Abstract
Neurofibromatosis type 1 (NF1) is a genetic disorder that is driven by the loss of neurofibromin (Nf) protein function. Nf contains a Ras-GTPase-activating protein domain, which directly regulates Ras signaling. Numerous clinical manifestations are associated with the loss of Nf and increased Ras activity. Ras proteins must be prenylated to traffic and functionally localize with target membranes. Hence, Ras is a potential therapeutic target for treating NF1. We have tested the efficacy of two novel farnesyl transferase inhibitors (FTIs), 1 and 2, alone or in combination with lovastatin, on two NF1 malignant peripheral nerve sheath tumor (MPNST) cell lines, NF90-8 and ST88-14. Single treatments of 1, 2, or lovastatin had no effect on Ras prenylation or MPNST cell proliferation. However, low micromolar combinations of 1 or 2 with lovastatin (FTI/lovastatin) reduced Ras prenylation in both MPNST cell lines. Furthermore, this FTI/lovastatin combination treatment reduced cell proliferation and induced an apoptotic response as shown by morphological analysis, procaspase-3/-7 activation, loss of mitochondrial membrane potential, and accumulation of cells with sub-G1 DNA content. Little to no detectable toxicity was observed in normal rat Schwann cells following FTI/lovastatin combination treatment. These data support the hypothesis that combination FTI plus lovastatin therapy may be a potential treatment for NF1 MPNSTs.
Footnotes
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This study was supported by the Department of the Army (Grants DAMD17-03-1-0182 and W81XWH-05-1-0193). J.W.W. and M.D.K. were supported by the National Institutes of Health Grant T32 ES012163. This project was aided by Imaging and Cytometry Core facilities that were supported by National Institutes of Health Grants P30 ES06639 and P30 CA22453.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.135830.
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ABBREVIATIONS: NF1, neurofibromatosis type 1; MPNST, malignant peripheral nerve sheath tumor; Nf, neurofibromin; GAP, GTPase-activating protein; FTI, farnesyl transferase inhibitor; HMG, hydroxymethylglutaryl; FTase, farnesyl transferase; JC-1, 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide; iSC, spontaneously immortal rat Schwann cell clone; pRb, retinoblastoma protein; ΔΨm, mitochondrial membrane potential; PBS, phosphate-buffered saline; DMSO, dimethyl sulfoxide.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received December 24, 2007.
- Accepted March 25, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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