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Titolo:
Sequence-selective DNA binding drugs mithramycin A and chromomycin A(3) are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons
Autore:
Chatterjee, S; Zaman, K; Ryu, H; Conforto, A; Ratan, RR;
Indirizzi:
Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA Harvard Univ Boston MA USA 02115 h Med, Dept Neurol, Boston, MA 02115 USA Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA Harvard Univ Boston MA USA 02115 , Neurosci Program, Boston, MA 02115 USA Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA Beth Israel Deaconess Med Ctr Boston MA USA 02215 r, Boston, MA 02215 USA
Titolo Testata:
ANNALS OF NEUROLOGY
fascicolo: 3, volume: 49, anno: 2001,
pagine: 345 - 354
SICI:
0364-5134(200103)49:3<345:SDBDMA>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROGRAMMED CELL-DEATH; AMYOTROPHIC-LATERAL-SCLEROSIS; NF-KAPPA-B; FOCAL CEREBRAL-ISCHEMIA; SV40 EARLY PROMOTER; TRANSCRIPTION FACTOR; PARKINSONS-DISEASE; C-JUN; SYMPATHETIC NEURONS; GLUTAMATE TOXICITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
65
Recensione:
Indirizzi per estratti:
Indirizzo: Ratan, RR Harvard Univ, Inst Med, Neurol Labs, 77 Ave Louis Pasteur, Boston, MA 02115 USA Harvard Univ 77 Ave Louis Pasteur Boston MA USA 02115 02115 USA
Citazione:
S. Chatterjee et al., "Sequence-selective DNA binding drugs mithramycin A and chromomycin A(3) are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons", ANN NEUROL, 49(3), 2001, pp. 345-354

Abstract

Global inhibitors of RNA or protein synthesis such as actinomycin D or cycloheximide abrogate neuronal apoptosis induced by numerous pathological stimuli in vitro and in vivo. The clinical application of actinomycin D or cycloheximide to human neurological disease has been limited by the toxicitiesof these agents. To overcome these toxicities, strategies must be developed to inhibit selectively the expression of deleterious proapoptotic proteins, while leaving the expression of antiapoptotic, proregeneration, and other critical homeostatic proteins unperturbed. Mithramycin A (trade name Plicamycin) is an aureolic acid antibiotic that has been used in humans to treat hypercalcemia and several types of cancers. This class of agents is believed to act, in part, by selectively inhibiting gene expression by displacing transcriptional activators that bind to G-C-rich regions of promoters. Here we demonstrate that mithramycin A and its structural analog chromomycin A3 are potent inhibitors of neuronal apopotosis induced by glutathione depletion-induced oxidative stress of the DNA-damaging agent camptothecin. We correlate the protective effects of mithramycin A with its ability to inhibit enhanced DNA binding of the transcription factors Sp1 andSp3 to their cognate "G-C" box induced by oxidative stress or DNA damage. The protective effects of mithramycin A cannot be attributed to global inhibition of proteinsynthesis. Together, these results suggest that mithramycin A and its structural analogs may be effective agents for the treatment of neurological diseases associated with aberrant activation of apoptosis and highlight the potential use of sequence-selective DNA-binding drugs as neurological therapeutics.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/04/20 alle ore 08:59:57