TY - JOUR
T1 - Inhibition of topoisomerase I function by coralyne and 5,6-dihydrocoralyne
AU - Wang, Li Kai
AU - Rogers, Brian D.
AU - Hecht, Sidney M.
PY - 1996
Y1 - 1996
N2 - The antitumor agent coralyne and a number of structural analogues were found to be inhibitors of DNA topoisomerase I and were characterized biochemically. Several of these analogues stabilized the covalent binary complex formed between calf thymus topoisomerase I and pSP64 plasmid DNA; coralyne and 5,6-dihydrocoralyne had the greatest potency as inhibitors in this assay. In common with camptothecin, the effects of coralyne and 5,6-dihydrocoralyne were reversed in the presence of increasing salt concentration or temperature, consistent with the interpretation that both functioned mechanistically in a fashion analogous to camptothecin. The sequence specificity of DNA cleavage by coralyne and 5,6-dihydrocoralyne was also studied in comparison with camptothecin using a 471-bp DNA duplex as a substrate for topoisomerase I. Seven sites of cleavage were apparent, four of which were shared in common by coralyne, 5,6-dihydrocoralyne and camptothecin. Coralyne and 5,6-dihydrocoralyne produced cleavage at one sequence, 5′-TCTC↓GTAA-3′, that was not apparent in the presence of camptothecin; correspondingly, two cleavage bands appeared only when camptothecin was present. Coralyne and 5,6-dihydrocoralyne also inhibited topoisomerase I-mediated relaxation of supercoiled plasmid DNA. Coralyne was the most potent inhibitor of DNA relaxation; the effects of camptothecin and 5,6-dihydrocoralyne were roughly equal. At high concentrations, coralyne completely suppressed the formation of the topoisomerase I-DNA covalent binary complex.
AB - The antitumor agent coralyne and a number of structural analogues were found to be inhibitors of DNA topoisomerase I and were characterized biochemically. Several of these analogues stabilized the covalent binary complex formed between calf thymus topoisomerase I and pSP64 plasmid DNA; coralyne and 5,6-dihydrocoralyne had the greatest potency as inhibitors in this assay. In common with camptothecin, the effects of coralyne and 5,6-dihydrocoralyne were reversed in the presence of increasing salt concentration or temperature, consistent with the interpretation that both functioned mechanistically in a fashion analogous to camptothecin. The sequence specificity of DNA cleavage by coralyne and 5,6-dihydrocoralyne was also studied in comparison with camptothecin using a 471-bp DNA duplex as a substrate for topoisomerase I. Seven sites of cleavage were apparent, four of which were shared in common by coralyne, 5,6-dihydrocoralyne and camptothecin. Coralyne and 5,6-dihydrocoralyne produced cleavage at one sequence, 5′-TCTC↓GTAA-3′, that was not apparent in the presence of camptothecin; correspondingly, two cleavage bands appeared only when camptothecin was present. Coralyne and 5,6-dihydrocoralyne also inhibited topoisomerase I-mediated relaxation of supercoiled plasmid DNA. Coralyne was the most potent inhibitor of DNA relaxation; the effects of camptothecin and 5,6-dihydrocoralyne were roughly equal. At high concentrations, coralyne completely suppressed the formation of the topoisomerase I-DNA covalent binary complex.
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U2 - 10.1021/tx950080y
DO - 10.1021/tx950080y
M3 - Article
C2 - 8924619
AN - SCOPUS:0030054013
SN - 0893-228X
VL - 9
SP - 75
EP - 83
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
IS - 1
ER -