title: Molecular basis of recognition of quadruplexes human telomere and c-myc promoter by the putative anticancer agent sanguinarine.
abstract: BACKGROUND
  Interaction of putative anticancer agent sanguinarine with two quadruplex forming sequences, human telomeric DNA (H24) and NHE III1 upstream of the P1 promoter of c-myc (Pu27), has been studied to understand the structural basis of the recognition.
  
  
  METHODS
  Absorption, fluorescence and circular dichroism spectroscopy have been employed to characterize the association. Energetics of the interaction was studied by isothermal titration and differential scanning calorimetry. TRAP assay was done to assess the inhibitory potential of sanguinarine.
  
  
  RESULTS
  Absorption and fluorescence studies show that sanguinarine has high binding affinity of ~10(5)M(-1) for both sequences. Binding stoichiometry is 2:1 for H24 and 3:1 for Pu27. Results suggest stacking interaction between planar sanguinarine moiety and G-quartets. Circular dichroism spectra show that sanguinarine does not cause structural perturbation in the all-parallel Pu27 but causes a structural transition from mixed hybrid to basket form at higher sanguinarine concentration in case of H24. The interaction is characterized by total enthalpy-entropy compensation and high heat capacity values. Differential scanning calorimetry studies suggest that sanguinarine binding increases the melting temperature and also the total enthalpy of transition of both quadruplexes. TRAP results show that sanguinarine effectively blocks telomerase activity in a concentration dependent manner in cell extracts from MDAMB-231 breast cancer cell lines.
  
  
  CONCLUSIONS
  These results suggest that there is a difference in the structural modes of association of sanguinarine to the quadruplexes.
  
  
  CONCLUSIONS
  It helps to understand the role of quadruplex structures as a target of small molecule inhibitors of telomerase.
authors.affiliation: Saha Institute of Nuclear Physics, Bidhan Nagar, Kolkata, India.
authors.forename: Saptaparni
authors.initials: S
authors.lastname: Ghosh
authors.forename: Suman Kalyan
authors.initials: SK
authors.lastname: Pradhan
authors.forename: Anirban
authors.initials: A
authors.lastname: Kar
authors.forename: Shantanu
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Dipak
authors.initials: D
authors.lastname: Dasgupta
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D053119:Benzophenanthridines / Q000494:pharmacology*; D002152:Calorimetry, Differential Scanning; D002942:Circular Dichroism; D005454:Fluorescence Polarization; D054856:G-Quadruplexes; D016259:Genes, myc; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D016615:Telomere
chemical_list: D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D007546:Isoquinolines; C005705:sanguinarine