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Interaction of doxorubicin with a regulatory element of hmga1 and its in vitro anti-cancer activity associated with decreased HMGA1 expression

Paper ID Volume ID Publish Year Pages File Format Full-Text
29836 44444 2014 11 PDF Available
Title
Interaction of doxorubicin with a regulatory element of hmga1 and its in vitro anti-cancer activity associated with decreased HMGA1 expression
Abstract

•Doxorubicin (DOX) exhibits stabilizing effect leading to strong complex formation between DOX and hmga1.•The binding of DOX to DNA is exothermic in nature favoured by negative enthalpy and positive entropy changes.•DOX causes significant downregulation of HNGA1 both at transcriptional as well as translational level.•DOX brings in its anti-cancer activity via intercalation resulting in regression in hmga1 expression.

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 (Ka, 5.2 × 105 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.

Keywords
hmga1; Doxorubicin; DNA-drug interaction; Spectroscopy; Thermodynamics
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Interaction of doxorubicin with a regulatory element of hmga1 and its in vitro anti-cancer activity associated with decreased HMGA1 expression
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Publisher
Database: Elsevier - ScienceDirect
Journal: Journal of Photochemistry and Photobiology B: Biology - Volume 141, December 2014, Pages 36–46
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
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Full-text PDF Download
Online Support
Any Questions? feel free to contact us