Lovastatin and phenylacetate induce apoptosis, but not differentiation, in human malignant glioma cells.
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.
Schmidt
F
F
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, School of Medicine, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany.
Groscurth
P
P
Kermer
M
M
Dichgans
J
J
Weller
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000494:pharmacology; D008854:Microscopy, Electron; D009154:Mutation / Q000502:physiology; D010648:Phenylacetates / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D010648:Phenylacetates; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D008148:Lovastatin