title: Interaction of doxorubicin with a regulatory element of hmga1 and its in vitro anti-cancer activity associated with decreased HMGA1 expression.
abstract: High mobility group A1 (HMGA1) non-histone chromatin protein is known as an architectural transcription factor that regulates transcription of various genes. HMGA1 is highly expressed in almost all human cancers and considered as a potent tumor marker. Because of its association with cancers, hmga1 is considered as a critical target for anti-cancer drugs. In the present study, we report interaction of doxorubicin (DOX) with a short deoxyoligonucleotide (-1917 to -1940) within a regulatory element of hmga1 and its subsequent effect on expression of HMGA1 in breast cancer MCF7 cells. Binding of DOX to DNA was found to be strong (K(a), 5.2 × 10(5)M(-1)) and thermodynamically favorable by both negative enthalpy (ΔH, -8.1 ± 0.25 kcal M(-1)) and positive entropy changes (TΔS, 21.1 ± 5.2 kcal M(-1)) at 20 °C. A significant increase in melting temperature of DNA in presence of DOX by +10 °C was accompanied by substantial quenching of fluorescence of DOX (∼ 85%) at 595 nm and hypochromic change (∼ 40%) at 500 nm absorption spectra of DOX along with a bathochromic shift of ∼ 5 nm. Reduced expression of HMGA1 by ∼ 60% both at mRNA and protein level and associated cell death in presence of DOX was observed in breast cancer cells. Therefore, hmga1 is a promising chemotherapeutic target in treating human malignancies.
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: zahidaasim@gmail.com.
authors.forename: Md Zahid
authors.initials: MZ
authors.lastname: Akhter
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: rajeswari3011@hotmail.com.
authors.forename: Moganty R
authors.initials: MR
authors.lastname: Rajeswari
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001483:Base Sequence; D002152:Calorimetry, Differential Scanning; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004317:Doxorubicin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D019277:Entropy; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D025741:HMGA1a Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional; D044366:Transition Temperature; D014466:Ultraviolet Rays
chemical_list: D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; D025741:HMGA1a Protein; D004317:Doxorubicin; D004247:DNA
keywords: DNA-drug interaction; Doxorubicin; Spectroscopy; Thermodynamics; hmga1