PMID- 12846580
OWN - NLM
STAT- MEDLINE
DCOM- 20030812
LR  - 20131121
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 42
IP  - 27
DP  - 2003 Jul 15
TI  - Inhibition of c-src transcription by mithramycin: structure-activity 
      relationships of biosynthetically produced mithramycin analogues using the c-src 
      promoter as target.
PG  - 8313-24
AB  - The aureolic acid antitumor antibiotic mithramycin (MTM) inhibits both cancer 
      growth and bone resorption by cross-linking GC-rich DNA, thus blocking binding of 
      Sp-family transcription factors to gene regulatory elements. Transcription of 
      c-src, a gene implicated in many human cancers and required for 
      osteoclast-dependent bone resorption, is regulated by the binding of Sp factors 
      to specific elements in its promoter. Therefore, this gene represents an 
      important anticancer target and a potential lead target through which MTM 
      displays its so far uncharacterized action against osteoclastic bone resorption. 
      Here we demonstrate, using DNA binding studies, promoter reporter assays, and 
      RT-PCR, that MTM inhibits Sp binding to the c-src promoter region, thereby 
      decreasing its expression in human cancer cells. Furthermore, selected 
      mithramycin analogues, namely, premithramycin B, mithramycin SK, 
      7-demethylmithramycin, 4E-ketomithramycin, and 4C-ketodemycarosylmithramycin, 
      generated through combinatorial biosynthesis, were compared with MTM for their 
      ability to block Sp binding to the c-src promoter. Although most of the tested 
      compounds lost their ability to bind to the DNA, alteration of the MTM 3-pentyl 
      side chain led to a compound (mithramycin SK) with the same DNA binding 
      specificity but with lower binding affinity than MTM. While this compound was 
      comparable to MTM in promoter reporter, gene expression, and anticancer assays, 
      given its weaker interaction with the DNA, it may be much less toxic than MTM. 
      The results presented here supplement recent findings and, moreover, allow new 
      conclusions to be made regarding both the structure-activity relationships, 
      particularly with respect to the alkyl side chains, and the mechanism of action 
      of aureolic acid drugs.
FAU - Remsing, Lily L
AU  - Remsing LL
AD  - Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 
      Lexington, Kentucky 40536, USA.
FAU - Bahadori, Hamid R
AU  - Bahadori HR
FAU - Carbone, Giuseppina M
AU  - Carbone GM
FAU - McGuffie, Eileen M
AU  - McGuffie EM
FAU - Catapano, Carlo V
AU  - Catapano CV
FAU - Rohr, Jurgen
AU  - Rohr J
LA  - eng
GR  - 1R01CA091901-01/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (DNA Primers)
RN  - 0 (Transcription Factors)
RN  - 9007-49-2 (DNA)
RN  - NIJ123W41V (Plicamycin)
SB  - IM
MH  - Antibiotics, Antineoplastic/*pharmacology
MH  - Base Sequence
MH  - DNA
MH  - DNA Primers
MH  - *Genes, src
MH  - Humans
MH  - Molecular Sequence Data
MH  - Plicamycin/*pharmacology
MH  - *Promoter Regions, Genetic
MH  - Structure-Activity Relationship
MH  - Transcription Factors/metabolism
MH  - Transcription, Genetic/*drug effects
MH  - Tumor Cells, Cultured
EDAT- 2003/07/09 05:00
MHDA- 2003/08/13 05:00
CRDT- 2003/07/09 05:00
PHST- 2003/07/09 05:00 [pubmed]
PHST- 2003/08/13 05:00 [medline]
PHST- 2003/07/09 05:00 [entrez]
AID - 10.1021/bi034091z [doi]
PST - ppublish
SO  - Biochemistry. 2003 Jul 15;42(27):8313-24. doi: 10.1021/bi034091z.