Molecular aspects on adriamycin interaction with hmga1 regulatory region and its inhibitory effect on HMGA1 expression in human cervical cancer. Issue 4 (2nd April 2016)

• Record Type: Journal Article
• Authors: Akhter, Md. Zahid; Luthra, Kalpana; Rajeswari, Moganty R.
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 34:Issue 4(2016)
• Page Start: 877
• Page End: 891
• Publication Date: 2016-04-02
• Subjects: adriamycin -- DNA–drug interaction -- spectroscopy -- thermodynamics -- hmga1 expression; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2015.1057617
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract : High mobility group A1 (HMGA1), a non-histone chromosomal protein, is highly expressed in a wide range of human cancers including cervical, breast, and prostate cancers. Therefore, hmga1 gene is considered as an attractive potential target for anticancer drugs. We have chosen 27 bp DNA sequence from a regulatory region of hmga1 promoter and studied its interaction with adriamycin (ADM) and in vitro expression of HMGA1 in the presence of ADM in HeLa cell line. A variety of biophysical techniques were employed to understand the characteristics of [DNA–ADM] complex. Spectrophotometric titration data, DNA denaturation profiles, and quenching of fluorescence of ADM in the presence of DNA demonstrated a strong complexation between DNA and ADM with a high binding affinity (Ka) of 1.3 × 10 6 M −1 and a stoichiometry of 1:3 (drug:nucleotide). The energetics of binding obtained from isothermal titration calorimetry and differential scanning calorimetry suggest the binding to be exothermic and enthalpy (∆ H, −6.7 ± 2.4 kcal M −1 ) and entropy ( T Δ S, 18.5 ± 6.4 kcal M −1 ) driven (20°C), which is typical of intercalative mode of binding. Further, results on decreased expression (by ~70%) of HMGA1 both at mRNA and protein levels in association with the observed cell death (by ~75%) in HeLa cell line, clearly confirm that ADM does target hmga1 ; however, the effect of ADM on genes other than hmga1 either directly or via hmga1 -mediated pathways cannot be ruled out in the observed cytotoxicity. Therefore, hmga1 in general and particularly the regulatory region is a promising target for therapeutic strategy in combating cancer.