title: Structural aspects of the interaction of anticancer drug Actinomycin-D to the GC rich region of hmgb1 gene.
abstract: The high mobility group box 1 protein has been identified as a key player in chromatin homeostasis including transcription regulation, recombination, repair, and chromatin remodeling. Emerging findings indicate HMGB1 protein over expression in nearly all types of human cancers and inflammatory disorders. Thus it is considered as a potential therapeutic target for treating various malignancies. We screened the promoter region of hmgb1 gene and selected a positive regulatory element of 25 base pair duplex (25RY) (-165 to -183) as a potential target for chemotherapeutic intervention. The molecular interaction of actinomycin (ACT) with the regulatory region of hmgb1 gene was characterized by spectroscopic, calorimetric and molecular docking studies. The hypochromic and bathochromic shift in the absorption spectrum, stabilization of 25RY duplex against thermal denaturation, perturbation of CD spectrum of duplex and enhancement of fluorescence intensity of actinomycin indicate strong binding of actinomycin to the hmgb1 promoter region (25RY).The energetics was characterized to be endothermic and entropy driven. All these results are in good agreement with in silico investigation that suggest minor groove binding with effective intercalation at GC bases of actinomycin to 25RY. This study identifies hmgb1 gene promoter region a potential target for the anticancer therapautiucs.
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: lohanineelam87@gmail.com.
authors.forename: Neelam
authors.initials: N
authors.lastname: Lohani
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India.
authors.forename: Himanshu Narayan
authors.initials: HN
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: rajeswari3011@hotmail.com.
authors.forename: R Rajeswari
authors.initials: RR
authors.lastname: Moganty
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D003609:Dactinomycin / Q000378:metabolism / Q000494:pharmacology*; D020862:GC Rich Sequence; D024243:HMGB1 Protein / Q000235:genetics*; D062105:Molecular Docking Simulation; D009690:Nucleic Acid Conformation / Q000187:drug effects; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D024243:HMGB1 Protein; D003609:Dactinomycin
keywords: Actinomycin-D; Drug–DNA interaction; HMGB1