Inhibition of protein farnesylation enhances the chemotherapeutic efficacyof the novel geranylgeranyltransferase inhibitor BAL9611 colon cancer cells

Proteins belonging to the ras superfamily are involved in cell proliferatio n of normal and neoplastic tissues. To be biologically active, they require post-translational isoprenylation by farnesyl-transferase and geranylgeran yl-transferase. Enzyme inhibition by drugs may thus represent a promising a pproach to the treatment of cancer. Therefore, the combined effect of BAL96 11, a novel inhibitor of geranylgeranylation, and manumycin, a farnesyl-tra nsferase inhibitor, was evaluated on the SW620 human colon cancer cell line which harbours a mutated K-ras gene. BAL9611 and manumycin dose-dependentl y inhibited SW620 cell growth with 50% inhibitory concentration (IC50) of 0 .47 +/- 0.03 and 5.24 +/- 1.41 muM (mean +/- SE), respectively. The isobolo gram analysis performed at the IC50 level revealed that the combined treatm ent was highly synergistic with respect to cell growth inhibition. BAL9611 and manumycin were able to inhibit the geranylgeranylation of p21 rhoA and farnesylation of p21 ras; both drugs inhibited p42ERK2/MAPK phosphorylation , but their combination was more effective than either drug alone. Moreover , the enhanced inhibition of cell growth in vitro by the BAL9611-manumycin combination was also observed in vivo in CD nu/nu female mice xenografted w ith SW620 tumours. Finally, both drugs were able to induce cell death by ap optosis in vitro and in vivo, as demonstrated by perinuclear chromatin cond ensation, cytoplasm budding and nuclear fragmentation, and interoligonucleo somal DNA digestion. In conclusion, the inhibition of protein farnesylation enhances the chemotherapeutic effect of BAL9611 in vitro and in vivo in a synergistic fashion, as a result of the impairment of post-translational is oprenylation of proteins and phosphorylation of p42ERK2/MAPK, whose activat ion is associated with post-translational geranylgeranylation and farnesyla tion of p21 rhoA and p21 ras. (C) 2001 Cancer Research Campaign.