The Ras inhibitor farnesylthiosalicylic acid as a potential therapy for neurofibromatosis type 1.
OBJECTIVE
Farnesylthiosalicylic acid (FTS) is a Ras inhibitor that dislodges all active Ras isoforms from the membrane. We assessed the ability of FTS to reverse the transformed phenotype of neurofibromatosis type 1 (NF1)-associated tumor cell lines of malignant peripheral nerve sheath tumor (MPNST).


METHODS
nf1 mutations were genotyped, allelic losses were analyzed, and neurofibromin expression levels were determined in MPNST cell lines ST88-14, S265P21, and 90-8. The effects of FTS on GTP-bound Ras (Ras-GTP) and its prominent downstream targets, as well as on cell morphology, anchorage-dependent and anchorage-independent growth, and tumor growth in mice, were assessed.


RESULTS
The MPNST cell lines were biallelic, NF1 inactive, and neurofibromin deficient. We show that FTS treatment shortened the relatively long duration of Ras activation and signaling to extracellular signal-regulated kinase, Akt, and RalA in all NF1-deficient MPNST cell lines (NF1 cells) to that observed in a non-NF1, normally expressing neurofibromin MPNST cell line. These effects of FTS led to lower steady-state levels of Ras-GTP and its activated targets. Both anchorage-dependent and anchorage-independent growth of NF1 cells were dose dependently inhibited by FTS, and the inhibition correlated positively with Ras-GTP levels. NF1 cells were found to possess strong actin stress fibers, and this phenotype was also corrected by FTS. NF1 tumor growth in a nude mouse model was inhibited by oral FTS.


CONCLUSIONS
FTS treatment of NF1 cells normalized Ras-GTP levels, resulting in reversal of the transformed phenotype and inhibition of tumor growth. FTS may therefore be considered as a potential drug for the treatment of NF1.
Barkan
Batya
B
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences and Sackler School of Medicine, Tel Aviv University, Tel Aviv, and The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Sheba Medical, Tel Hashomer, Israel.
Starinsky
Sigal
S
Friedman
Eitan
E
Stein
Reuven
R
Kloog
Yoel
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects; D004341:Drug Evaluation; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016514:Genes, Neurofibromatosis 1 / Q000502:physiology; D011905:Genes, ras / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000188:drug therapy* / Q000235:genetics; D025542:Neurofibromin 1 / Q000235:genetics; D012459:Salicylates / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D025542:Neurofibromin 1; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D018631:ras Proteins