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.