Peptidomimetic inhibitors of Ras farnesylation and function in whole cells.

Pharmacological inhibition of Ras-transformed epithelial cell growth is linked to down-regulation of epidermal growth factor–related peptides

“…The development of FTIs has provided an important tool for studying Ras function and signal transduction. Although FTIs are effective inhibitors of H-Ras transformation in vitro and in vivo, [11][12][13][14][15][16][17][18] the lack of an effect in K-Ras-transformed cells and the apparent lack of effects on normal cell signaling suggest that further study of mechanisms underlying FTI drug action is needed. We previously found that activated Ras is capable of transforming RIE-1 cells, whereas activated Raf is not.…”

“…37 Parental RIE-1 cells, as well as control transfectants and activated Raf-transfected RIE-1 cells, are unaffected by L744,832 treatment, consistent with previous reports showing that normal cells and cells transfected with oncogenes downstream of Ras signaling are resistant to the effects of FTIs. [11][12][13][14][15][16][17][18] The specificity of FTIs for transformed cells is puzzling because Ras function is important in normal mitogenic signaling and is dependent on farnesylation. It is feasible that normal Ras signaling occurs by geranylgeranylated K-Ras in the presence of FTase inhibition.…”

“…1 Because Ras mutations occur in many human tumors, including adenocarcinomas of the pancreas and colon, [8][9][10] specific FTase inhibitors (FTIs) have been developed as anticancer drugs to target tumors in which Ras proteins have undergone mutational activation. [11][12][13][14][15] Pharmacological inhibition of FTase has been shown to inhibit Ras in both H-and K-Ras-transformed cells, although in most cell types, K-Ras is far less sensitive. 11,12,[15][16][17][18][19] Resistance of K-Ras to FTIs may occur because of its compensatory geranylgeranylation by GGPTase I.…”

Aberrant Function of the Ras-Related Protein TC21/R-Ras2 Triggers Malignant Transformation

“…Cells were transfected with, per dish, 10 ng (NIH 3T3) or 2 ,ug (Rat-1) of pZIP plasmid DNAs encoding normal or mutant TC21 or Ras protein. Transformed foci were quantitated after 14 days (NIH 3T3) or 22 days (Rat-1). Rat-1 cultures were stained with 0.4% crystal violet to better visualize transformed foci.…”

“…Like Ras, TC21 is prenylated and membrane associated, and it is likely that, as for Ras, these properties are necessary for TC21 transforming activity. Therefore, if TC21 is found to contribute to human cancers, such tumors would be good candidates for treatment with prenylation inhibitors such as the CAAX-based peptidomimetic compounds that have recently been shown to be powerful and specific inhibitors of the growth of Ras-transformed cells in vitro (22,26,31).…”