PMID- 11261509
OWN - NLM
STAT- MEDLINE
DCOM- 20010419
LR  - 20220318
IS  - 0364-5134 (Print)
IS  - 0364-5134 (Linking)
VI  - 49
IP  - 3
DP  - 2001 Mar
TI  - Sequence-selective DNA binding drugs mithramycin A and chromomycin A3 are potent 
      inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in 
      cortical neurons.
PG  - 345-54
AB  - 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 toxicities of 
      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 
      apoptosis induced by glutathione depletion-induced oxidative stress or 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 and Sp3 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 protein synthesis. 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.
FAU - Chatterjee, S
AU  - Chatterjee S
AD  - Department of Neurology, Harvard Medical School and The Beth Israel-Deaconess 
      Medical Center, Boston, MA, USA.
FAU - Zaman, K
AU  - Zaman K
FAU - Ryu, H
AU  - Ryu H
FAU - Conforto, A
AU  - Conforto A
FAU - Ratan, R R
AU  - Ratan RR
LA  - eng
GR  - K08 NS019151/NS/NINDS NIH HHS/United States
GR  - R01 NS39170/NS/NINDS NIH HHS/United States
GR  - R29 NS34943/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Ann Neurol
JT  - Annals of neurology
JID - 7707449
RN  - 97666-60-9 (mithramycin A)
RN  - DVW027E7NL (Chromomycin A3)
RN  - NIJ123W41V (Plicamycin)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Base Sequence
MH  - Brain/*metabolism
MH  - Cell Culture Techniques
MH  - Chromomycin A3/*metabolism
MH  - DNA Damage/*drug effects
MH  - Electrophoresis/methods
MH  - Microscopy, Phase-Contrast
MH  - Neurodegenerative Diseases/*metabolism
MH  - Neurons/cytology/*drug effects/*metabolism
MH  - Oxidative Stress/*drug effects
MH  - Plicamycin/*analogs & derivatives/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
EDAT- 2001/03/23 10:00
MHDA- 2001/04/21 10:01
CRDT- 2001/03/23 10:00
PHST- 2001/03/23 10:00 [pubmed]
PHST- 2001/04/21 10:01 [medline]
PHST- 2001/03/23 10:00 [entrez]
PST - ppublish
SO  - Ann Neurol. 2001 Mar;49(3):345-54.