s-trans-trans-farnesylthiosalicylic-acid and Skin-Neoplasms

The constitutive activity of a number of growth and cell survival pathways are thought to contribute to the inherent resistance of melanoma to chemotherapy and radiotherapy. Many of these pathways are driven through the small GTPase Ras. Novel drugs such as the farnesyl transferase inhibitors (FTIs) and farnesyl thiosalicylic acid (FTS) interfere with the signaling of oncogenic Ras. The aim of our study was to assess the anti-tumour activity of the FTI SCH66336 in melanoma and to assess whether SCH66336 and FTS could modulate chemoresistance in melanoma cells. SCH66336 had marked anti-proliferative activity in both human and mouse melanoma cell lines, but not in non-transformed NIH 3T3 cells. The anti-proliferative activity of SCH66336 was due to G1-phase cell cycle arrest and retinoblastoma protein inactivation, followed by apoptosis. Cisplatin, when administered alone, induced little apoptosis. In combination with cisplatin, both FTS and SCH66336 markedly enhanced the level of cisplatin-induced apoptosis, an effect that was associated with enhanced G2/M cell cycle arrest. Pharmacological inhibitors of either ERK or PI-3 kinase/Akt did not mimic the chemosensitising activity of either SCH66336 or FTS. In summary, our study demonstrates that SCH66336 has good in vitro anti-tumour activity in both human and mouse melanoma cell lines, and suggests that Ras antagonists could be useful in overcoming chemoresistance to cisplatin in melanoma.

Topics: 3T3 Cells; Actins; Alkyl and Aryl Transferases; Animals; Apoptosis; Blotting, Western; Cell Cycle; Cell Division; Cisplatin; Colony-Forming Units Assay; Drug Synergism; Enzyme Inhibitors; Farnesol; Farnesyltranstransferase; Humans; In Situ Nick-End Labeling; In Vitro Techniques; Melanoma; Mice; Microscopy, Confocal; Mitogen-Activated Protein Kinases; Piperidines; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Pyridines; Retinoblastoma Protein; Salicylates; Skin Neoplasms; Tumor Cells, Cultured

Merkel cell carcinoma (MCC) is a neuroendocrine malignancy showing poor response to a variety of therapeutic strategies. We evaluated the antitumor activity of S-trans, trans-farnesylthiosalicylic acid (FTS), a new inhibitor of Ras signal transduction, in a newly established SCID mouse xenotransplantation model for human MCC (seven animals per group). FTS injected intraperitoneally at 5 mg/kg per day for 2 weeks up-regulated the tumor suppressor p53 and induced tumor cell apoptosis in established MCCs growing subcutaneously in SCID mice. These effects led to a statistically significant inhibition of MCC growth (P<0.002). The mean tumor weights following FTS or control treatment were 0.32+/-0.15 g and 1.08+/-0.29 g, respectively. There was no evidence of FTS related toxicity at the effective dose used. Our findings stress the notion that FTS may qualify as a novel and rational treatment approach for MCC and possibly for other tumors that rely on tyrosine kinase signaling.

Topics: Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Merkel Cell; Cell Division; Farnesol; Female; Humans; Injections, Intraperitoneal; Male; Mice; Mice, SCID; Proto-Oncogene Proteins p21(ras); Salicylates; Skin Neoplasms; Statistics, Nonparametric; Transplantation, Heterologous; Tumor Cells, Cultured; Tumor Suppressor Protein p53