Lovastatin and phenylacetate induce apoptosis, but not differentiation, inhuman malignant glioma cells

Induction of differentiation is an attractive approach to the management of infiltrative tumors such as malignant glioma. Here, we report that lovasta tin and phenylacetate induce apoptosis, but fail to induce differentiation, in malignant glioma cell lines and untransformed rat astrocytes. Lovastati n and phenylacetate promote p21 accumulation but fail to induce cell cycle arrest. BCL-2 gene transfer inhibits apoptosis induced by lovastatin but no t apoptosis induced by phenylacetate. Wildtype p53 gene transfer promotes l ovastatin-induced apoptosis in p53 wild-type LN-229 cells but not in p53 mu tant T98G cells. Phenylacetate-induced apoptosis is attenuated by wild-type p53 gene transfer in both cell lines. Neither lovastatin nor phenylacetate modulate glioma cell sensitivity to CD95 ligand-induced apoptosis or cance r chemotherapy. Thus, this study provides no rationale for clinical trials of lovastatin or phenylacetate in the differentiation therapy of malignant glioma. We conclude that neoplastic glioma cells as well as untransformed r at astrocytes are refractory to the induction of differentiation by lovasta tin and phenylacetate.