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

  • Mazet J
  • Padieu M
  • Osman H
 et al. 
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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 μM inhibited very efficiently the [3H]farnesyl but not [3H]geranylgeranyl transfer to Ras. However, proliferation of these cells was only slightly sensitive to RPR130401 (IC50=30 μM). GGTI-298 inhibited the growth of these cells with an IC50of 11 μM but cell lysis was observed at 15 μM. The combination of 10 μM RPR130401 and 10 μM GGTI-298 inhibited efficiently (80%) cell proliferation. These combined inhibitors but not each inhibitor alone blocked the cell cycle in G0/G1and 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. Copyright (C) 1999 Federation of European Biochemical Societies.

Author-supplied keywords

  • Alternative pathway
  • Anti-proliferative effect
  • Farnesyltransferase
  • Geranylgeranyltransferase
  • Kirsten-Ras
  • Prenylation

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  • Jean Luc Mazet

  • Martine Padieu

  • Hanan Osman

  • Gabrielle Maume

  • Patrick Mailliet

  • Norbert Dereu

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