Pharmaceutical Sciences Faculty Publications

Title

Farnesylthiosalicylic Acid Induces Caspase Activation and Apoptosis in Glioblastoma Cells

Document Type

Article

Publication Date

4-2006

Journal Title

Cell Death & Differentiation

ISSN

1350-9047

Volume

13

Issue

4

First Page

642

Last Page

651

DOI

http://dx.doi.org/10.1038/sj.cdd.4401783

PubMed ID

16239932

Abstract

Primary glioblastomas (GBMs) commonly overexpress the oncogene epidermal growth factor receptor (EGFR), which leads to increased Ras activity. FTA, a novel Ras inhibitor, produced both time- and dose-dependent caspase-mediated apoptosis in GBM cell lines. EGFR-mediated increase in 3H-thymidine uptake was inhibited by FTA. FACS analysis was performed to determine the percent of apoptotic cells. The sub-Go population of GBM cells was increased from 4.5 to 13.8% (control) to over 45–53.6% in FTA-treated cells within 24 h. Furthermore, FTA also increased the activities of both caspase-3 and -9, and PARP cleavage. Treatment of GBMs with FTA before or after EGF addition to the cultures blocked phosphorylation of Akt and mitogen-activated protein kinases (MAPK). FTA also significantly reduced the amount of EGF-induced Ras-GTP as reflected by a decrease in the level of Ras bound to Raf-RBD-GST. This study demonstrates that inhibition of Ras methylation may provide a therapeutic target for the treatment of GBMs overexpressing EGFR.

Keywords

Glioblastoma, farnesylthiosalicylic acid, apoptosis, epidermal growth factor receptor, Ras, caspase