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

Acta Neuropathol. 2001 Mar;101(3):217-24. doi: 10.1007/s004010000254.

Abstract

Induction of differentiation is an attractive approach to the management of infiltrative tumors such as malignant glioma. Here, we report that lovastatin and phenylacetate induce apoptosis, but fail to induce differentiation, in malignant glioma cell lines and untransformed rat astrocytes. Lovastatin and phenylacetate promote p21 accumulation but fail to induce cell cycle arrest. BCL-2 gene transfer inhibits apoptosis induced by lovastatin but not apoptosis induced by phenylacetate. Wild-type p53 gene transfer promotes lovastatin-induced apoptosis in p53 wild-type LN-229 cells but not in p53 mutant 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 cancer 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 rat astrocytes are refractory to the induction of differentiation by lovastatin and phenylacetate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / ultrastructure
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / physiopathology
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cell Differentiation / drug effects*
  • Cell Differentiation / physiology
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Dose-Response Relationship, Drug
  • Drug Interactions / physiology
  • Fas Ligand Protein
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / physiology
  • Glial Fibrillary Acidic Protein / metabolism
  • Glioma / drug therapy*
  • Glioma / metabolism
  • Glioma / physiopathology
  • Humans
  • Lovastatin / pharmacology*
  • Membrane Glycoproteins / pharmacology
  • Microscopy, Electron
  • Mutation / physiology
  • Phenylacetates / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Transfection
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / ultrastructure
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • FASLG protein, human
  • Fas Ligand Protein
  • Faslg protein, rat
  • Glial Fibrillary Acidic Protein
  • Membrane Glycoproteins
  • Phenylacetates
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p53
  • Lovastatin