Inhibition of Ras and Related G-Proteins As a Therapeutic Strategy for Blocking Malignant Glioma Growth

Inhibition of Ras and Related G-Proteins As a Therapeutic Strategy for Blocking Malignant Glioma... AbstractOBJECTIVE:Preliminary studies have demonstrated that the Ras family and related guanosine 5'-triphosphatedependent 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.METHODS AND RESULTS:METHODS AND RESULTS: 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 xmol/L. We then assessed the effect of prenylation inhibition on cell viability using clonogenic growth assays. This demonstrated a steady drop in the number of colonies with increasing drug concentrations for all three inhibitors. Third, we examined whether the cytotoxic effects of one of these inhibitors (GGTI-298) were associated with the induction of apoptosis using a terminal transferase-catalyzed in situ end-labeling technique. This approach showed a time-dependent increase in apoptotic cell numbers, which correlated with a progressive decrease in the percentage of cells that were viable as assessed by trypan blue exclusion.CONCLUSION:Our studies demonstrated that FTI-277, GGTI-286, and GGTI-298 each yielded significant antiproliferative effects in human malignant glioma cells in vitro at low micromolar concentrations, which have been achievable in vivo without major systemic toxicity. Extended periods of drug treatment produced cytotoxicity in the tumor cells, which correlated with the induction of apoptosis. We conclude that inhibition of Ras and related G-proteins offers a promising approach for blocking glioma proliferation that justifies further investigation in vivo. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Inhibition of Ras and Related G-Proteins As a Therapeutic Strategy for Blocking Malignant Glioma Growth

Inhibition of Ras and Related G-Proteins As a Therapeutic Strategy for Blocking Malignant Glioma Growth

EXPERIMENTAL STUDIES Inhibition of Ras and Related G-Proteins As a Therapeutic Strategy for Blocking Malignant Glioma Growth Markus Bredel, Cand.Med., Ian F. Pollack, M.D., John M. Freund, B.S., Andrew D. Hamilton, Ph.D., Said M. Sebti, Ph.D. Department of Neurosurgery (MB, IFP, IMF), University of Pittsburgh Cancer Institute Brain Tumor Center, University of Pittsburgh School of Medicine and the Children's Hospital of Pittsburgh; Department of Chemistry (A D H ), University of Pittsburgh, Pittsburgh, Pennsylvania; and Drug Discovery Program (SMS), H. Lee Moffitt Cancer Center, Department of Biochemistry and Molecular Biology, University of South Florida, Tampa, Florida O BJECTIVE: 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. M ETH O D S A N D RESULTS: 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 (G G TI-286 and G G TI-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, G G TI-2 8 6 , and G G T I-2 9 8 each produced a striking concentration-dependent antiprolif­ erative effect on the glioma cell lines, with the median effective dose ranging from 2.5 to 15.5 ^xmol/L. We then assessed the effect of prenylation inhibition on...
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Publisher
Congress of Neurological Surgeons
Copyright
© Published by Oxford University Press.
ISSN
0148-396X
eISSN
1524-4040
D.O.I.
10.1097/00006123-199807000-00081
Publisher site
See Article on Publisher Site

Abstract

AbstractOBJECTIVE:Preliminary studies have demonstrated that the Ras family and related guanosine 5'-triphosphatedependent 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.METHODS AND RESULTS:METHODS AND RESULTS: 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 xmol/L. We then assessed the effect of prenylation inhibition on cell viability using clonogenic growth assays. This demonstrated a steady drop in the number of colonies with increasing drug concentrations for all three inhibitors. Third, we examined whether the cytotoxic effects of one of these inhibitors (GGTI-298) were associated with the induction of apoptosis using a terminal transferase-catalyzed in situ end-labeling technique. This approach showed a time-dependent increase in apoptotic cell numbers, which correlated with a progressive decrease in the percentage of cells that were viable as assessed by trypan blue exclusion.CONCLUSION:Our studies demonstrated that FTI-277, GGTI-286, and GGTI-298 each yielded significant antiproliferative effects in human malignant glioma cells in vitro at low micromolar concentrations, which have been achievable in vivo without major systemic toxicity. Extended periods of drug treatment produced cytotoxicity in the tumor cells, which correlated with the induction of apoptosis. We conclude that inhibition of Ras and related G-proteins offers a promising approach for blocking glioma proliferation that justifies further investigation in vivo.

Journal

NeurosurgeryOxford University Press

Published: Jul 1, 1998

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