Role of caspases and CD95/Fas in the apoptotic effects of a nucleotide analog PMEG in CCRF-CEM cells
Language English Country Greece Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
20683014
PII: 30/7/2791
Knihovny.cz E-resources
- MeSH
- Enzyme Activation MeSH
- fas Receptor metabolism MeSH
- Apoptosis drug effects physiology MeSH
- Cell Cycle drug effects physiology MeSH
- Cyclin E biosynthesis genetics MeSH
- Cyclin-Dependent Kinases biosynthesis metabolism MeSH
- Guanine analogs & derivatives pharmacology MeSH
- Cyclin-Dependent Kinase Inhibitor Proteins biosynthesis metabolism MeSH
- Caspases metabolism MeSH
- Humans MeSH
- Membrane Potential, Mitochondrial drug effects MeSH
- Mitochondria drug effects physiology MeSH
- Cell Line, Tumor MeSH
- Oncogene Proteins biosynthesis genetics MeSH
- Organophosphorus Compounds pharmacology MeSH
- S Phase drug effects MeSH
- Signal Transduction MeSH
- T-Lymphocytes cytology drug effects enzymology metabolism MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 9-((2-phosphonylmethoxy)ethyl)guanine MeSH Browser
- fas Receptor MeSH
- CCNE1 protein, human MeSH Browser
- Cyclin E MeSH
- Cyclin-Dependent Kinases MeSH
- FAS protein, human MeSH Browser
- Guanine MeSH
- Cyclin-Dependent Kinase Inhibitor Proteins MeSH
- Caspases MeSH
- Oncogene Proteins MeSH
- Organophosphorus Compounds MeSH
BACKGROUND/AIM: 9-[2-(phosphonomethoxy)ethyl] guanine (PMEG) is a guanine acyclic nucleotide analog whose targeted prodrugs are being investigated for chemotherapy of lymphomas. Its antiproliferative effects have been attributed to cell cycle arrest and induction of apoptosis, however, the underlying mechanisms remain poorly understood. The objective of this study was to determine the requirements for caspase and CD95/Fas activation in PMEG-induced apoptosis. Additionally, the influence of PMEG on cell cycle regulatory proteins was explored. MATERIALS AND METHODS: CCRF-CEM cells were exposed to PMEG with/without caspase inhibitor or anti-Fas blocking antibody and assayed for phosphatidyl serine externalization, mitochondrial depolarization and the cleavage of procaspase 3 and the nuclear protein poly (ADP-ribose) polymerase (PARP). RESULTS: Despite an observed increase of caspase 3, 8 and 9 proteolytic activity, neither pretreatment of the cells with cell-permeable caspase inhibitors nor blocking the death receptor with anti-Fas antibody did prevent apoptosis induced by PMEG. CONCLUSION: PMEG-induced apoptosis is caspase- and CD95/Fas-independent.
