Once again, solitary treatments of DMSO, 500 nM 1 or 2 2, or 500 nM lovastatin had no detectable toxicity. loss of mitochondrial membrane potential, and build up 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. Intro Neurofibromatosis Type 1 (NF1) E3 ligase Ligand 10 is definitely a genetically inherited syndrome E3 ligase Ligand 10 that affects approximately 1:3000 individuals (Arun and Gutmann, 2004). NF1 presents with an array of medical manifestations that can arise during early development through adulthood, including improved pigmentation of the skin (caf au lait macules), Lisch nodules of the iris, learning disabilities, and irregular development of the skeletal system (Lynch and Gutmann, 2002). NF1 is definitely characterized by the development of benign peripheral nerve sheath tumors (BPNST) or neurofibromas. Approximately 10% of NF1 individuals experience tumor transformation to the more aggressive malignant peripheral nerve sheath tumors (MPNST) (Ward and Gutmann, 2005). Progression toward MPNST is definitely a leading cause of improved mortality for NF1 individuals. Therapies are limited to excision of neurofibromas, radiation of plexiform neurofibromas, and the use of cytotoxic compounds. Although excision of tumors is the primary Mouse monoclonal to GLP form of treatment, the tumors tend to return (Packer et al., 2002). A molecularly targeted therapy designed against the molecular background of NF1 may reveal more effective methods for treatment of NF1 (Dilworth et al., 2006). The molecular pathogenesis of NF1 was better recognized following the finding of the gene, which encodes the protein neurofibromin (Nf). Nf consists of a Ras GTPase activating protein (Ras-GAP) website (DeClue et al., 1991). This website is responsible for controlling Ras signaling by increasing the intrinsic rate of Ras hydrolysis, therefore converting the active Ras-GTP to the inactive Ras-GDP form (Eccleston et al., 1993). Germline mutations of the gene result in reduced Nf manifestation and a loss of Ras-GAP activity. The consequence of dropping E3 ligase Ligand 10 Ras-GAP activity is definitely aberrant Ras signaling that can potentially lead to the development of NF1 (Basu et al., 1992; Feldkamp et al., 1999). Our lab and others have previously targeted downstream signaling partners of Ras by treating MPNST cell lines with MEK inhibitors (Tang et al., 1998; Chadee and Kyriakis, 2004; Mattingly et al., 2006; Roth et al., 2007). We have demonstrated that PD184352 (CI-1040) induced apoptosis in MPNST cell lines, confirming the dependence of the Ras-MAPK pathway with this disease (Mattingly et al., 2006). Ras proteins E3 ligase Ligand 10 are translated in the cytoplasm as inactive precursor molecules that must undergo a series of post-translational modifications before the protein can fully function (Gibbs et al., 2001). The 1st necessary step is the covalent addition of a prenyl group, either a 15C farnesyl or a 20C geranylgeranyl group, to the C-Terminal CaaX package (Basso et al., 2006). Reducing the prenylation of proteins to treat NF1 has been recognized as a potential restorative approach. For example, the farnesyl transferase inhibitor (FTI) BMS-186511 reduces proliferation of MPNST cell collection ST88-14 (Yan et al., 1995), and FTI L-739-749 reduces proliferation of Nf-deficient mouse Schwann cells (Kim et al., 1997). A phase I medical trial utilizing FTI tipifarnib to treat plexiform neurofibromas was tolerated well in children, but no objective reactions were accomplished (Widemann et al., 2006). Although this study offers advanced to an ongoing Phase II trial (NCT00029354), it is likely that further development of this treatment approach will be required. Our lab is definitely interested in utilizing FTIs and lovastatin, an inhibitor of the HMG-CoA reductase, to reduce prenylation of proteins like a potential therapy for several diseases. We have previously reported that lovastatin, in combination with FTI 3-allylfarnesol, induces relocation of RhoB from your membrane portion to the cytosolic portion following treatment in A10 vascular clean muscle mass cells. The translocation of RhoB from your membrane to the cytosol is the result of inhibiting RhoB prenylation (Mattingly et al., 2002). A prodrug analog of 3-allylfarnesol phosphate was also shown to inhibit RhoB prenylation in STS-26T.