Ras Protein Farnesyltransferase: A Strategic Target for Anticancer Therapeutic Development

Abstract

Ras proteins are guanine nucleotide-binding proteins that play pivotal roles in the control of normal and transformed cell growth and are among the most intensively studied proteins of the past decade. After stimulation by various growth factors and cytokines, Ras activates several downstream effectors, including the Raf-1/mitogen-activated protein kinase pathway and the Rac/Rho pathway. In approximately 30% of human cancers, including a substantial proportion of pancreatic and colon adenocarcinomas, mutated ras genes produce mutated proteins that remain locked in an active state, thereby relaying uncontrolled proliferative signals. Ras undergoes several posttranslational modifications that facilitate its attachment to the inner surface of the plasma membrane. The first-and most critical-modification is the addition of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). It follows that inhibiting FTase would prevent Ras from maturing into its biologically active form, and FTase is of considerable interest as a potential therapeutic target. Different classes of FTase inhibitors have been identified that block farnesylation of Ras, reverse Ras-mediated cell transformation in human cell lines, and inhibit the growth of human tumor cells in nude mice. In transgenic mice with established tumors, FTase inhibitors cause regression in some tumors, which appears to be mediated through both apoptosis and cell cycle regulation. FTase inhibitors have been well tolerated in animal studies and do not produce the generalized cytotoxic effects in normal tissues that are a major limitation of most conventional anticancer agents. There are ongoing clinical evaluations of FTase inhibitors to determine the feasibility of administering them on dose schedules like those that portend optimal therapeutic indices in preclinical studies. Because of the unique biologic aspects of FTase, designing disease-directed phase II and III evaluations of their effectiveness presents formidable challenges.

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

“…However, it has been suggested previously that N-BP-induced apoptosis in other cell types may be associated with impaired prenylation of key cellular proteins. Prenylation of Ras is required for its normal membrane localisation and function (Rowinsky et al, 1999).…”

Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines

“…Further examination of a number of human cancer cell lines may provide a clearer picture of apoptosis in cancer cells concerning which type of treatment will be e ective in inducing apoptosis of these cell lines. These results are relevant, since FTI is currently evaluated in clinical trials (Rowinsky et al, 1999). Moasser et al (1998) pointed out that the e cacy of FTI can be improved by combining with a second drug.…”

“…In some cases, regression of tumor growth was induced by FTI Liu et al, 1998;Norgaard et al, 1999). FTI is currently being evaluated in clinical trials (Rowinsky et al, 1999).…”

Farnesylthiosalicylic acid induces caspase activation and apoptosis in glioblastoma cells

“…Unlike gliomas that rarely have Ras mutations, prostate cancers and melanoma have a higher incidence of Ras mutations. 39 The rarity of Ras mutations in glioma makes this tumor a more appropriate target for Ras inhibition with probably low incidence of resistance to chemotherapy, as long as these tumors are tyrosine kinase receptor activated Ras-dependent. When this paper was under review, Blum et al 40 published a paper showing two of the GBM cell lines (U-87 MG and U-373 MG) used in our studies expressed N-Ras, H-Ras and K-Ras.…”