Combination of the novel farnesyltransferase inhibitor RPR130401 and the geranylgeranyltransferase-1 inhibitor GGTI-298 disrupts MAP kinase activation and G1-S transition in Ki-Ras-overexpressing transformed adrenocortical cells

To test the Kirsten-Ras (Ki-Ras) alternative prenylation hypothesis in malignant transformation, we used a novel farnesyltransferase inhibitor competitive to farnesyl-pyrophosphate, RPR130401,and a CaaX peptidomimetic geranylgeranyltransferase-1 inhibitor GGTI-298, In Ki-Ras-overexpressing transformed adrenocortical cells, RPR130401 at 1-10 mu M inhibited very efficiently the [H-3]farnesyl but not [H-3]geranylgeranyl transfer to Ras, However, proliferation of these cells was only slightly sensitive to RPR130401 (IC50 = 30 mu M). GGTI-298 inhibited the growth of these cells with an IC50 of 11 mu M but cell lysis was observed at 15 mu M. The combination of 10 mu M RPR130401 and 10 mu M GGTI-298 inhibited efficiently (80%) cell proliferation. These combined inhibitors but not each inhibitor alone blocked the cell cycle in G(0)/G(1) and disrupted MAP kinase activation. Thus, combination of two inhibitors, at non-cytotoxic concentrations, acting on the farnesyl-pyrophosphate binding site of the farnesyltransferase and the CaaX binding site of the geranylgeranyltransferase-1 respectively is an efficient strategy for disrupting Ki-Ras tumorigenic cell proliferation, (C) 1999 Federation of European Biochemical Societies.