A comprehensive approach to ascertain the binding mode of curcumin with DNA

Haris, P.; Mary, Varughese; Aparna, P.; Dileep, Kalarickal V.; Sudarsanakumar, C.

doi:10.1016/j.saa.2016.11.049

Cited by 33 publications

(10 citation statements)

References 69 publications

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“…The thermodynamic parameters obtained from ITC indicate that the binding of luteolin with ctDNA is favorable; the reaction is exothermic and enthalpy-driven, also costing in entropic contribution. The ITC values are in agreement with some reported values of minor groove binding drugs. − …”

Section: Resultssupporting

confidence: 90%

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Experimental Probing and Molecular Dynamics Simulation of the Molecular Recognition of DNA Duplexes by the Flavonoid Luteolin

Mary

Haris

Mathai

et al. 2017

J. Chem. Inf. Model.

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Luteolin (CHO) is an important flavonoid found in many fruits, plants, medicinal herbs, and vegetables exhibiting many pharmacological properties. The anticancer, antitumor, antioxidant, and anti-inflammatory activities of luteolin have been reported. The pharmacological action of small molecules is dependent upon its interaction with biomacromolecules. The interactions of small molecules with DNA play a major role in the transcription and translation process. In this work, we explored the energetic profile of DNA-luteolin interaction by isothermal titration calorimetry (ITC). The effect of temperature and salt concentration on DNA binding was examined by UV-Vis method. The mode of interaction was further probed by UV melting temperature analysis and differential scanning calorimetry. An atomic level insight on the recognition of luteolin with DNA was achieved by employing molecular dynamics (MD) simulation on luteolin in complex with AT- and GC-rich DNA sequences. AMBER force field proves to be appropriate in providing an understanding on the binding mode and specificity of luteolin with duplex DNA. MD results suggest a minor groove binding of luteolin with DNA and the binding free energy obtained is in agreement with the experimental results.

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Section: Resultssupporting

confidence: 90%

“…The binding constant of luteolin with ctDNA is calculated upon the change in the concentration of ctDNA keeping the concentration of luteolin constant, using the following host− guest equation: 57,58 3…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Experimental Probing and Molecular Dynamics Simulation of the Molecular Recognition of DNA Duplexes by the Flavonoid Luteolin

Mary

Haris

Mathai

et al. 2017

J. Chem. Inf. Model.

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“…Therefore, it is very likely that ligand-L will also bind with DNA/Cu(II) in in vivo conditions. Our results of high binding constant (~ 10 3 M -1 ) are supported by the studies present in literature where it was shown that curcumin (binding constant with DNA: 2.97 × 10 3 M -1 ) causes DNA damage in cancer cells and also inhibits tumor growth in in vitro and in vivo xenograft model [ 92 – 94 ].…”

Section: Discussionsupporting

confidence: 89%

Synthesis of novel coumarin nucleus-based DPA drug-like molecular entity: In vitro DNA/Cu(II) binding, DNA cleavage and pro-oxidant mechanism for anticancer action

Khan

Malla²,

Zafar

et al. 2017

PLoS ONE

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Despite substantial research on cancer therapeutics, systemic toxicity and drug-resistance limits the clinical application of many drugs like cisplatin. Therefore, new chemotherapeutic strategies against different malignancies are needed. Targeted cancer therapy is a new paradigm for cancer therapeutics which targets pathways or chemical entities specific to cancer cells than normal ones. Unlike normal cells, cancer cells contain elevated copper which plays an integral role in angiogenesis. Copper is an important metal ion associated with chromatin DNA, particularly with guanine. Thus, targeting copper via copper-specific chelators in cancer cells can serve as an effective anticancer strategy. New pharmacophore di(2-picolyl)amine (DPA)-3(bromoacetyl) coumarin (ligand-L) was synthesized and characterized by IR, ESI-MS, 1H- and 13C-NMR. Binding ability of ligand-L to DNA/Cu(II) was evaluated using a plethora of biophysical techniques which revealed ligand-L-DNA and ligand-L-Cu(II) interaction. Competitive displacement assay and docking confirmed non-intercalative binding mode of ligand-L with ctDNA. Cyclic voltammetry confirmed ligand-L causes quasi reversible Cu(II)/Cu(I) conversion. Further, acute toxicity studies revealed no toxic effects of ligand-L on mice. To evaluate the chemotherapeutic potential and anticancer mechanism of ligand-L, DNA damage via pBR322 cleavage assay and reactive oxygen species (ROS) generation were studied. Results demonstrate that ligand-L causes DNA cleavage involving ROS generation in the presence of Cu(II). In conclusion, ligand-L causes redox cycling of Cu(II) to generate ROS which leads to oxidative DNA damage and pro-oxidant cancer cell death. These findings will establish ligand-L as a lead molecule to synthesize new molecules with better copper chelating and pro-oxidant properties against different malignancies.

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“…Several studies have shown that curcumin can modulate a variety of cancer-related targets or pathways [ 102 , 103 , 109 , 110 ], which may be responsible for its effectiveness in combating cancer diseases. Recent studies demonstrate that curcumin’s mechanism of action includes: (i) modulation of CYP enzymes by elevation of transcription factor Nrf2 level via the mitogen-activated protein kinase (MAPK) signaling pathway and Akt pathway [ 111 ]; (ii) mitotic catastrophe induction due to caspase activation and mitochondrial membrane polarization [ 14 ]; (iii) promotion of autophagic cell death, an important death inducer in apoptosis resistant cancer cells by beclin-1-dependent and independent pathways [ 14 , 112 ]; (iv) arrest of the cell cycle at the check points G1, S-phase and G2/M phase, modulating the cell cycle regulators, including upregulation of cyclin-dependent kinase inhibitors (CDKIs) [ 113 ]; (v) promotion of the inhibition of transcription factor NF-κB by preventing nuclear translocation of NF-κB and attenuating the DNA binding ability of NF-κB, contouring the problem of chemoresistance [ 114 ]; (vi) promotion of the inhibition of the crucial steps to angiogenesis by downregulation of the PGDF, VEGF and FGF expression and downregulation of MMPs via NF-κB, ERKs, MAPKs, PKC and PI3K inhibition [ 115 ]; and (vii) inhibiting tubulin polymerization, that is curcumin binds with DNA [ 116 , 117 ]. Despite this knowledge about curcumin’s multiple mechanisms of action, its biological properties are not fully understood.…”

Section: Secondary Metabolites From Plants As Anticancer Agentsmentioning

confidence: 99%

Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application

Seca

Pinto

2018

IJMS

534

303

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Cancer is a multistage process resulting in an uncontrolled and abrupt division of cells and is one of the leading causes of mortality. The cases reported and the predictions for the near future are unthinkable. Food and Drug Administration data showed that 40% of the approved molecules are natural compounds or inspired by them, from which, 74% are used in anticancer therapy. In fact, natural products are viewed as more biologically friendly, that is less toxic to normal cells. In this review, the most recent and successful cases of secondary metabolites, including alkaloid, diterpene, triterpene and polyphenolic type compounds, with great anticancer potential are discussed. Focusing on the ones that are in clinical trial development or already used in anticancer therapy, therefore successful cases such as paclitaxel and homoharringtonine (in clinical use), curcumin and ingenol mebutate (in clinical trials) will be addressed. Each compound’s natural source, the most important steps in their discovery, their therapeutic targets, as well as the main structural modifications that can improve anticancer properties will be discussed in order to show the role of plants as a source of effective and safe anticancer drugs.

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A comprehensive approach to ascertain the binding mode of curcumin with DNA

Cited by 33 publications

References 69 publications

Experimental Probing and Molecular Dynamics Simulation of the Molecular Recognition of DNA Duplexes by the Flavonoid Luteolin

Experimental Probing and Molecular Dynamics Simulation of the Molecular Recognition of DNA Duplexes by the Flavonoid Luteolin

Synthesis of novel coumarin nucleus-based DPA drug-like molecular entity: In vitro DNA/Cu(II) binding, DNA cleavage and pro-oxidant mechanism for anticancer action

Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application

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