Farnesyl transferase inhibitor SCH66336 is cytostatic, pro-apoptotic and enhances chemosensitivity to cisplatin in melanoma cells.

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.

Smalley KS ，Eisen TG 《INTERNATIONAL JOURNAL OF CANCER》

Effects of insulin-like growth factor binding protein-3 and farnesyltransferase inhibitor SCH66336 on Akt expression and apoptosis in non-small-cell lung cancer cells.

Lee HY ，Moon H ，Chun KH ，Chang YS ，Hassan K ，Ji L ，Lotan R ，Khuri FR ，Hong WK ... -  《-》

Farnesyl thiosalicylic acid inhibits the growth of melanoma cells through a combination of cytostatic and pro-apoptotic effects.

Novel classes of drug that interfere with the signalling of the small G-protein Ras, the so-called Ras antagonists, are showing much promise as novel anti-cancer agents. In this study, we demonstrate that the novel Ras antagonist farnesylthiosalicylic acid (FTS) inhibits the growth of Colo 853 melanoma cells through a combination of cytostatic and pro-apoptotic effects. Furthermore, these phenomena are seen under conditions of cell attachment and in the presence of serum. Treatment of Colo 853 cells with FTS led to time-dependent inhibition of constitutive Akt, retinoblastoma protein (pRB) and ERK activity, with a concurrent loss of Akt expression. Inhibition of Akt and ERK activity induces apoptosis in other human cancer cell lines. Here it is demonstrated that inhibition of Akt, or ERK and Akt in combination, leads to cell cycle arrest but not apoptosis in melanoma cells. FTS treatment was also found to upregulate activity of the stress-activated p38 MAP kinase. Inhibition of p38 MAP kinase, using the selective inhibitor SB 203580, followed by FTS treatment, significantly increased the proportion of apoptotic cells after 72 hr, possibly suggesting a modulatory role for p38 MAP kinase in FTS-induced melanoma cell apoptosis.

Smalley KS ，Eisen TG 《INTERNATIONAL JOURNAL OF CANCER》

Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia.

Peters DG ，Hoover RR ，Gerlach MJ ，Koh EY ，Zhang H ，Choe K ，Kirschmeier P ，Bishop WR ，Daley GQ ... -  《BLOOD》

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects.

Feldkamp MM ，Lau N ，Guha A 《ONCOGENE》