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Titolo:
INDUCTION OF NEURONAL APOPTOSIS BY CAMPTOTHECIN, AN INHIBITOR OF DNA TOPOISOMERASE-I - EVIDENCE FOR CELL CYCLE-INDEPENDENT TOXICITY
Autore:
MORRIS EJ; GELLER HM;
Indirizzi:
UNIV MED & DENT NEW JERSEY,ROBERT WOOD JOHNSON MED SCH,DEPT PHARMACOL,675 HOES LANE PISCATAWAY NJ 08854
Titolo Testata:
The Journal of cell biology
fascicolo: 3, volume: 134, anno: 1996,
pagine: 757 - 770
SICI:
0021-9525(1996)134:3<757:IONABC>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
NERVE GROWTH-FACTOR; PC12 CELLS; CYTOSINE-ARABINOSIDE; SYMPATHETIC NEURONS; COCKAYNE-SYNDROME; CORTICAL-NEURONS; RNA-SYNTHESIS; MACROMOLECULAR-SYNTHESIS; IONIZING-RADIATION; FACTOR DEPRIVATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
71
Recensione:
Indirizzi per estratti:
Citazione:
E.J. Morris e H.M. Geller, "INDUCTION OF NEURONAL APOPTOSIS BY CAMPTOTHECIN, AN INHIBITOR OF DNA TOPOISOMERASE-I - EVIDENCE FOR CELL CYCLE-INDEPENDENT TOXICITY", The Journal of cell biology, 134(3), 1996, pp. 757-770

Abstract

Camptothecin is an S-phase-specific anticancer agent that inhibits the activity of the enzyme DNA topoisomerase-I (topo-I). Irreversible DNA double-strand breaks are produced during DNA synthesis in the presence of camptothecin, suggesting that this agent should not be toxic to nondividing cells, such as neurons. Unexpectedly, camptothecin inducedsignificant, dose-dependent cell death of postmitotic rat cortical neurons in vitro; astrocytes were more resistant. Aphidicolin, an inhibitor of DNA polymerase or, did not prevent camptothecin-induced neuronal death, while death was prevented by actinomycin D and 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole as well as cycloheximide and anisomycin, inhibitors of RNA and protein synthesis, respectively. Camptothecin-induced neuronal death was apoptotic, as characterized by chromatin condensation, cytoplasmic shrinking, plasma membrane blebbing, and fragmentation of neurites. DNA fragmentation was also confirmed by theuse of the in situ DNA end labeling assay, In addition, aurintricarboxylic acid, an inhibitor of the apoptotic endonuclease, partially protected against camptothecin-induced neuronal death. The toxicity of stereoisomers of a camptothecin analogue was stereospecific, demonstrating that toxicity was a result of inhibition of topo-I. The difference in sensitivity to camptothecin between neurons and astrocytes correlated with their transcriptional activity and level of topo-I protein expression. These data indicate important roles for topo-I in postmitotic neurons and suggest that topo-I inhibitors can induce apoptosis independent of DNA synthesis, We suggest a model based on transcriptionally mediated DNA damage, a novel mechanism of action of topo-I poisons.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/11/20 alle ore 06:05:35