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Combination of the novel farnesyltransferase inhibitor RPR130401 and the geranylgeranyltransferase‐1 inhibitor GGTI‐298 disrupts MAP kinase activation and G 1 ‐S transition in Ki‐Ras‐overexpressing transformed adrenocortical cells
Author(s) -
Mazet Jean-Luc,
Padieu Martine,
Osman Hanan,
Maume Gabrielle,
Mailliet Patrick,
Dereu Norbert,
Hamilton Andrew D,
Lavelle François,
Sebti Saïd M,
Maume Bernard F
Publication year - 1999
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(99)01355-1
Subject(s) - farnesyltransferase , prenylation , farnesyl pyrophosphate , farnesyltransferase inhibitor , farnesyl diphosphate farnesyltransferase , cell growth , chemistry , rho kinase inhibitor , biochemistry , kinase , pharmacology , biology , enzyme , atp synthase , rho associated protein kinase
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 [ 3 H]farnesyl but not [ 3 H]geranylgeranyl transfer to Ras. However, proliferation of these cells was only slightly sensitive to RPR130401 (IC 50 =30 μM). GGTI‐298 inhibited the growth of these cells with an IC 50 of 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 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.