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CELLULAR AND MOLECULAR

Induction of Apoptosis in Neurofibromatosis Type 1 Malignant Peripheral Nerve Sheath Tumor Cell Lines by a Combination of Novel Farnesyl Transferase Inhibitors and Lovastatin

Department of Pharmacology (J.W.W., D.T.L., J.J.R., R.R.M.) and Institute of Environmental Health Sciences (M.D.K., J.J.R.) and Environmental Health Sciences Center in Molecular and Cellular Toxicology with Human Applications (J.J.R., R.R.M.), Wayne State University, Detroit, Michigan; Medicinal Chemistry and Molecular Pharmacology and Cancer Center, Purdue University, West Lafayette, Indiana (F.F., R.A.G., R.F.B.); and Barbara Ann Karmanos Cancer Institute, Programs in Proteases (J.J.R.) and Molecular Biology and Human Genetics (R.R.M.), Detroit, Michigan

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.

Address correspondence to: Dr. Raymond R. Mattingly, Department of Pharmacology, Wayne State University, 540 East Canfield Ave., Detroit, MI 48201. E-mail: r.mattingly{at}wayne.edu

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