s-trans-trans-farnesylthiosalicylic-acid and Cell-Transformation--Neoplastic

A lipophilic farnesyl moiety attached to the carboxyl terminal cysteine of ras proteins structurally supports their membrane anchorage, required for ras-dependent growth-factor signaling and for transforming activity of ras oncoproteins. It has been shown that inhibition of ras farnesylation can block tumor growth in nude mice but that some ras-dependent tumors escape such blockage as a result of prenylation of ras. S-trans-transfarnesylthiosalicylic acid (FTS) is a potent ras-dislodging antagonist that does not affect ras prenylation but rather acts on the mature, membrane-bound ras and facilitates its degradation. Here we demonstrate that FTS induces reappearance of stress fibers in H-ras-transformed rat-1 cells (EJ cells) in vitro, inhibits their anchorage-independent growth in vitro, and blocks EJ-tumor growth in nude mice. The anchorage-independent growth of cells expressing ErbB2 (B104), but not that of v-raf-transformed cells, is also inhibited by FTS, suggesting specificity towards activated ras. FTS treatment (5 mg/kg i.p. daily) caused inhibition (75-80%) of tumor growth in nude mice implanted with EJ, but not in mice implanted with v-raf-transformed cells, with no evidence of systemic toxicity. Moreover, FTS treatment increased the survival rate of EJ-tumor-bearing mice from 48 to 68 days. Here we demonstrate anti-tumor potency in a synthetic, non-toxic, ras-dislodging antagonist acting independently of farnesyltransferases.

Topics: 3T3 Cells; Actins; Animals; Antineoplastic Agents; Cell Division; Cell Transformation, Neoplastic; Cytoskeleton; Farnesol; Genes, erbB-2; Genes, ras; Male; Mice; Mice, Nude; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms, Experimental; Neuroblastoma; Oncogene Proteins v-raf; Protein Prenylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins p21(ras); Rats; Receptor, ErbB-2; Retroviridae Proteins, Oncogenic; Salicylates; Substrate Specificity; Tumor Cells, Cultured