RPR-115135, a new non peptidomimetic farnesyltransferase inhibitor, induces G0/G1 arrest only in serum starved cells.
A new non peptidomimetic farnesyltransferase inhibitor, RPR-115135, was studied in an isogenic cell model system consisting of human colon cancer HCT-116 line. HCT-116 cells were transfected with an empty control pCMV vector or with a dominant-negative mutated p53 transgene to disrupt p53 function. Growth inhibitory effects of RPR-115135 were evaluated on cells growing under different conditions (serum starvation, serum starvation and recovery, nocodazole treatment). The cytotoxic activity of RPR-115135 was independent of the cell cycle status of the target cells. Addition of RPR-115135 only to cells exposed to reduced serum conditions (0.1% FCS) resulted in an enhanced ability of HCT-116 cells to arrest in the G0/G1 phase. This arrest response appeared independent of p53/p21cip1/waf-1 function. A reduction of Cyclin A protein amount by RPR-115135 was observed in both clones. These latter results suggest that RPR-115135 might down-regulate the cell cycle factor that would normally impede G0/G1 arrest.
Molecular Pathology Section, Laboratory of Experimental Oncology, National Cancer Research Institute, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. patrusso@hp380.ist.unige.it
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Russo
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Ottoboni
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Crippa
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JF
Riou
P M
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O'Connor
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D016895:Culture Media, Serum-Free / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005434:Flow Cytometry; D016158:Genes, p53; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009154:Mutation; D015739:Nocodazole / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D016895:Culture Media, Serum-Free; D016213:Cyclins; D004791:Enzyme Inhibitors; D007211:Indoles; C426728:RPR115135; D016159:Tumor Suppressor Protein p53; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D015739:Nocodazole