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.
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 microM 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 microM). GGTI-298 inhibited the growth of these cells with an IC(50) of 11 microM but cell lysis was observed at 15 microM. The combination of 10 microM RPR130401 and 10 microM 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.
Mazet
J L
JL
Unité Mixte de Recherche INRA-Université de Bourgogne, Phytopharmacie et Biochimie des Interactions Cellulaires, INRA, BV 1540, 21034, Dijon, France.
Padieu
M
M
Osman
H
H
Maume
G
G
Mailliet
P
P
Dereu
N
N
Hamilton
A D
AD
Lavelle
F
F
Sebti
S M
SM
Maume
B F
BF
D000311:Adrenal Glands / Q000378:metabolism; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D011905:Genes, ras / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D017368:Protein Prenylation / Q000187:drug effects; D051381:Rats; D016196:S Phase / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology; D013997:Time Factors; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; C102521:GGTI 298; D007211:Indoles; C400543:RPR 130401; D008148:Lovastatin; D019821:Simvastatin; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins