Farnesyltransferase inhibitor, R115777, reverses the resistance of human glioma cell lines to ionizing radiation.
We investigated for the first time the ability of farnesyltransferase inhibitors (FTI) to radiosensitize human glioma. For this, human glioma cell lines were treated with the specific FTI, R115777, 48 hr prior to a 2Gy irradiation. The treatment with R115777 decreased by 45% the SF2 value of the more radioresistant glioma cell lines (SF763 and U87) without any significant effect on the radioresistance of the radiosensitive ones (SF767 and U251-MG). This radiosensitizer effect was due to the induction of post-mitotic necrotic cell death. We then tested the hypothesis that wild-type Ras or RhoB, which has been proposed as potential FTI target, could control the glioma radioresistance. For this, we expressed inducible dominant negative forms of Ras (RasN17) and RhoB (RhoBN19) in radioresistant U87 glioma cell line and analyzed the survival after irradiation of the obtained clones. While blocking Ras pathways by expression of RasN17 did not affect the SF2 value of the U87 glioma cell line, the expression of RhoBN19 dramatically reduced the cell survival after irradiation of these cells. Taken together, these data demonstrated that RhoB, but not Ras, is implicated in glioma radioresistance. Furthermore, the R115777 differential radiosensitizer effect underlines the potential therapeutic interest of using this drug as a radiosensitizer of human glioma.
Delmas
Caroline
C
Laboratoire d'Oncologie Cellulaire et Moléculaire, Centre de Lutte Contre le Cancer Claudius Regaud, Toulouse Cedex, France.
Heliez
Christophe
C
Cohen-Jonathan
Elizabeth
E
End
Dave
D
Bonnet
Jacques
J
Favre
Gilles
G
Toulas
Christine
C
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D015870:Gene Expression; D011905:Genes, ras / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D009154:Mutation; D015363:Quinolones / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000502:physiology; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000502:physiology
D004791:Enzyme Inhibitors; D015363:Quinolones; D011838:Radiation-Sensitizing Agents; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins; D020743:rhoB GTP-Binding Protein; C402769:tipifarnib