Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

While 25% of human cancers harbor oncogenic Ras mutations, such mutations a re not found in astrocytomas. We have previously demonstrated that the acti vation of receptor tyrosine kinases expressed by malignant human astrocytom a cells and specimens results in functional upregulation of the Ras signall ing pathway and increased levels of activated Ras GTP. Farnesyl transferase inhibitors (FTIs) are promising anti-cancer agents in early clinical trial s, which may exert their effect through pharmacological inhibition of the R as signalling pathway, In this study we establish the anti-tumorigenic prop erties of the FTI L-744,832 against a panel of malignant human astrocytoma cell Lines. Furthermore, we demonstrate the multiple mechanisms by which L7 44,832 exerts its effect. L-744,832 demonstrates both cytostatic and cytoto xic effects on astrocytoma cells, and cells expressing a truncated constitu tively phosphorylated Epidermal Growth Factor Receptor common in high-grade astrocytomas (EGFRvIII/p140(EGF-R)) demonstrate increased sensitivity to t he agent. L-744,832 is capable of inducing apoptosis in astrocytoma cells u nder anchorage-dependent conditions; this process occurs in a p53-independe nt manner and is associated with increased expression of Bax and Bak, L-744 ,832 also induces cell cycle arrest at both the G(1)/M and G(2)/S checkpoin ts; this process is also independent of p53 mutational status. Cell cycle a rrest in drug-treated cells can be accompanied by induction of p21(WAF1/CIP 1), but this induction is not necessary for the cell cycle inhibitory effec ts, nor is it dependent on functional p53, Finally, angiogenesis in astrocy tomas has been shown to be dependent on secretion of Vascular Endothelial G rowth Factor (VEGF) by tumour cells, particularly under hypoxic conditions, L-744,832 potently inhibits the secretion of VEGF under hypoxic conditions . These combinations of mechanisms suggest that these tumours, despite the absence of oncogenic Ras mutations, will be amenable to growth inhibition b y FTIs, through a combination of anti-proliferative, pro-apoptotic, and ant i-angiogenic effects.