1. Induction of apoptosis and chemosensitization of mesothelioma cells by Bcl-2 and Bcl-xL antisense treatment.
- Author
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Hopkins-Donaldson S, Cathomas R, Simões-Wüst AP, Kurtz S, Belyanskaya L, Stahel RA, and Zangemeister-Wittke U
- Subjects
- Antimetabolites, Antineoplastic pharmacology, Antineoplastic Agents pharmacology, Blotting, Western, Caspases metabolism, Cell Division drug effects, Cisplatin pharmacology, Combined Modality Therapy, DNA Primers chemistry, Deoxycytidine pharmacology, Down-Regulation physiology, Humans, Lung Neoplasms genetics, Lung Neoplasms metabolism, Lung Neoplasms therapy, Membrane Potentials drug effects, Mesothelioma genetics, Mesothelioma metabolism, Mitochondria drug effects, Pleural Neoplasms genetics, Pleural Neoplasms metabolism, Polymerase Chain Reaction, Proto-Oncogene Proteins c-bcl-2 genetics, Ribonucleotide Reductases antagonists & inhibitors, Tumor Cells, Cultured, bcl-X Protein, Gemcitabine, Apoptosis drug effects, Deoxycytidine analogs & derivatives, Drug Resistance, Neoplasm physiology, Gene Expression Regulation, Neoplastic, Mesothelioma therapy, Oligonucleotides, Antisense pharmacology, Pleural Neoplasms therapy, Proto-Oncogene Proteins c-bcl-2 metabolism
- Abstract
Our study was designed to investigate the role of the anti-apoptotic proteins Bcl-2 and Bcl-xL in the chemoresistance of cells derived from malignant pleural mesothelioma. First, we determined the basal expression levels of Bcl-2 and Bcl-xL in mesothelioma cells and examined the effect of their downregulation by antisense oligonucleotides. Bcl-xL mRNA and protein could be readily detected in mesothelioma cell lines, whereas only low levels of Bcl-2 mRNA and protein were found. Preferential downregulation of either Bcl-xL alone or of Bcl-xL and Bcl-2 simultaneously was achieved by treatment with antisense oligonucleotides 4259 and 4625, respectively, whereas the expression of other apoptosis-relevant genes remained unaffected. Treatment with oligonucleotides 4259 or 4625 lowered the apoptosis threshold in ZL34 mesothelioma cells, as indicated by an increase in cell death accompanied by increased caspase-3-like activity, a decrease of the mitochondrial transmembrane potential and the cleavage of procaspase-7 and ICAD. In addition to the direct induction of apoptosis, antisense treatment sensitized ZL34 cells to the cytostatic effect of cisplatin and gemcitabine, with the combination of 4625 and cisplatin being the most effective. Our results demonstrate that Bcl-2 and Bcl-xL antisense treatment facilitates apoptosis in mesothelioma cells and suggest the use of Bcl-2/Bcl-xL bispecific antisense treatment in combination with cisplatin or gemcitabine for therapy of malignant pleural mesothelioma., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2003
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