Erucylphosphocholine-induced apoptosis in chemoresistant glioblastoma cell lines: involvement of caspase activation and mitochondrial alterations.
Intrinsic chemoresistance constitutes a major problem in the therapy of malignant gliomas. In vitro experiments with four astrocytoma/glioblastoma (AC/GBM) cell lines revealed that the chemoresistance of two cell lines, A172 and T98G, to cisplatin and etoposide was due to resistance to drug-induced apoptosis. In contrast, all the AC/GBM cell lines tested were sensitive to treatment with the lipophilic ether lipid erucylphosphocholine, ErPC. ErPC-induced apoptosis was independent of wild-type p53-signaling and triggering of the CD95/CD95 ligand (CD95L) system. Inhibition of protein and RNA synthesis by cycloheximide and actinomycin D did not abrogate ErPC-induced apoptosis. However, expression of members of the bcl-2 protein family was modulated during ErPC treatment. Activation of caspase 3 and mitochondrial alterations were central to ErPC-induced apoptosis. We conclude that ErPC-induced activation of the mitochondrial pathway enables cell death in the chemoresistant AC/GBM cells.
Jendrossek
V
V
Department of Physiology, University of Tübingen, Medical School, Germany. verena.jendrossek@uni-tuebingen.de
Kugler
W
W
Erdlenbruch
B
B
Eibl
H
H
Lang
F
F
Lakomek
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001254:Astrocytoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D053222:Fas Ligand Protein; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein; D019014:fas Receptor / Q000502:physiology
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor; D010767:Phosphorylcholine; C075010:erucylphosphocholine; D005047:Etoposide; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin