Nonpeptidomimetic farnesyltransferase inhibitor RPR-115135 increases cytotoxicity of 5-fluorouracil: role of p53.
A new nonpeptidic farnesyltransferase inhibitor, RPR-115135, in combination with 5-fluorouracil (5-FU) was studied in an isogenic cell line model system consisting of human colon cancer HCT-116 cells. HCT-116 cells were transfected with an empty control pCMV vector and with a dominant-negative mutated p53 transgene (248R/W). We found that, relative to control transfectants, there was a slight tendency for the p53 inactivated cells to be less sensitive to 5-FU after 6 days of continuous treatment. Simultaneous administration of RPR-115135 and 5-FU, at equitoxic concentrations, resulted in an enhancement of 5-FU cytotoxicity, especially in the CMV-2 clone. Growth inhibition could be accounted for on the basis of a specific cell cycle arrest phenotype (G(2)-M arrest in CMV-2 and S arrest in mutated clones), as assayed by flow cytometry. The combination RPR-115135 + 5-FU increases apoptotic events only in the CMV-2 clone.
Russo
Patrizia
P
Laboratory of Molecular Pharmacology, Division Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. patrizia.russo@istge.it
Ottoboni
Cristina
C
Malacarne
Davide
D
Crippa
Alessandra
A
Riou
Jean-Francois
JF
O'Connor
Patrick M
PM
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D010641:Phenotype; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D007211:Indoles; C426728:RPR115135; D016159:Tumor Suppressor Protein p53; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D005472:Fluorouracil