Inhibition of Ras and related G-proteins as a therapeutic strategy for blocking malignant glioma growth

Neurosurgery
M BredelS M Sebti

Abstract

Preliminary studies have demonstrated that the Ras family and related guanosine 5'-triphosphate-dependent proteins (G-proteins) are overactivated in malignant gliomas and may function as indirect mediators of glial transformation initiated by deregulated upstream signaling elements. We postulated that inhibiting the activation of such proteins might represent a promising strategy for blocking the aberrant proliferation of these tumors. Accordingly, we examined the therapeutic efficacy against malignant glioma cells in vitro of a series of selective peptidomimetic inhibitors of farnesylation (FTI-277) and geranylgeranylation (GGTI-286 and GGTI-298), which are critical steps in the post-translational processing (prenylation) of these proteins. We first defined concentration-response relationships for each of these agents, using MTS-based cell proliferation assays in the established malignant glioma cell lines U-87 and LN-Z308 and the low-passage malignant glioma cell line SG-388. FTI-277, GGTI-286, and GGTI-298 each produced a striking concentration-dependent antiproliferative effect on the glioma cell lines, with the median effective dose ranging from 2.5 to 15.5 micromol/L. We then assessed the effect of prenylation inhibition ...Continue Reading

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