Spectroscopic probing of recognition of the G-quadruplex in c-kit promoter by small-molecule natural products

Cui, Xiaojie; Lin, Senjie; Yuan, Gu

doi:10.1016/j.ijbiomac.2012.02.029

Cited by 33 publications

(35 citation statements)

References 23 publications

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“…Chelerythrine exhibited broad spectrum of cytotoxic activity against different types of cancer cell with minimal toxicity33. It was previously reported that Chelerythrine was recognized by human telomeric DNA and RNA G-quadruplex along with c-KIT promoter934. In this study for the first time we have shown Chelerythrine down regulates the expression of BCL2, VEGFA and KRAS genes.…”

supporting

confidence: 57%

“…These are known as six hallmarks of cancer7. These important events are linked with G-quadruplex forming gene promoters including c-MYC8, c-KIT9 and KRAS10 (self-sufficiency), RB1 (insensitivity), BCL211 (evasion of apoptosis), VEGFA (angiogenesis)12 hTERT (limitless replication)13 and PDGFA (metastasis). G-quadruplex structures in oncogenic promoters are indicators of the six hallmarks of cancer.…”

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confidence: 99%

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Chelerythrine down regulates expression of VEGFA, BCL2 and KRAS by arresting G-Quadruplex structures at their promoter regions

Jana

Mondal

Bhattacharjee

et al. 2017

Sci Rep

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A putative anticancer plant alkaloid, Chelerythrine binds to G-quadruplexes at promoters of VEGFA, BCL2 and KRAS genes and down regulates their expression. The association of Chelerythrine to G-quadruplex at the promoters of these oncogenes were monitored using UV absorption spectroscopy, fluorescence anisotropy, circular dichroism spectroscopy, CD melting, isothermal titration calorimetry, molecular dynamics simulation and quantitative RT-PCR technique. The pronounced hypochromism accompanied by red shifts in UV absorption spectroscopy in conjunction with ethidium bromide displacement assay indicates end stacking mode of interaction of Chelerythrine with the corresponding G-quadruplex structures. An increase in fluorescence anisotropy and CD melting temperature of Chelerythrine-quadruplex complex revealed the formation of stable Chelerythrine-quadruplex complex. Isothermal titration calorimetry data confirmed that Chelerythrine-quadruplex complex formation is thermodynamically favourable. Results of quantative RT-PCR experiment in combination with luciferase assay showed that Chelerythrine treatment to MCF7 breast cancer cells effectively down regulated transcript level of all three genes, suggesting that Chelerythrine efficiently binds to in cellulo quadruplex motifs. MD simulation provides the molecular picture showing interaction between Chelerythrine and G-quadruplex. Binding of Chelerythrine with BCL2, VEGFA and KRAS genes involved in evasion, angiogenesis and self sufficiency of cancer cells provides a new insight for the development of future therapeutics against cancer.

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supporting

confidence: 57%

mentioning

confidence: 99%

Chelerythrine down regulates expression of VEGFA, BCL2 and KRAS by arresting G-Quadruplex structures at their promoter regions

Jana

Mondal

Bhattacharjee

et al. 2017

Sci Rep

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“…It may be mentioned that there is an earlier report of the association of CHL with a nontelomeric quadruplex with a difference sequence, d(AGGGAGGGCGCT-GGGAGGAGGG). 31 This report showed the binding using ESI-MS and CD followed by an in silico autodock3. However, this report does not indicate any ligand-induced aggregation of the G-quadruplex, nor does it demonstrate telomerase inhibitory potential by TRAP assay.…”

Section: ■ Discussionmentioning

confidence: 99%

Plant Alkaloid Chelerythrine Induced Aggregation of Human Telomere Sequence—A Unique Mode of Association between a Small Molecule and a Quadruplex

et al. 2015

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Small molecules that interact with G-quadruplex structures formed by the human telomeric region and stabilize them have the potential to evolve as anticancer therapeutic agents. Herein we report the interaction of a putative anticancer agent from a plant source, chelerythrine, with the human telomeric DNA sequence. It has telomerase inhibitory potential as demonstrated from telomerase repeat amplification assay in cancer cell line extract. We have attributed this to the quadruplex binding potential of the molecule and characterized the molecular details of the interaction by means of optical spectroscopy such as absorbance and circular dichroism and calorimetric techniques such as isothermal titration calorimetry and differential scanning calorimetry. The results show that chelerythrine binds with micromolar dissociation constant and 2:1 binding stoichiometry to the human telomeric DNA sequence. Chelerythrine association stabilizes the G-quadruplex. Nuclear magnetic resonance spectroscopy ((1)H and (31)P) shows that chelerythrine binds to both G-quartet and phosphate backbone of the quadruplex leading to quadruplex aggregation. Molecular dynamics simulation studies support the above inferences and provide further insight into the mechanism of ligand binding. The specificity toward quartet binding for chelerythrine is higher compared to that of groove binding. MM-PBSA calculation mines out the energy penalty for quartet binding to be -4.7 kcal/mol, whereas that of the groove binding is -1.7 kcal/mol. We propose that the first chelerythrine molecule binds to the quartet followed by a second molecule which binds to the groove. This second molecule might bring about aggregation of the quadruplex structure which is evident from the results of nuclear magnetic resonance.

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“…1) is an alkaloid of this group isolated from the natural herb, greater celandine Chelidonium majus L. This compound is a potent, selective, and cell permeable protein kinase C (PKC) inhibitor that does not inhibit tyrosine protein kinases, cAMP-dependent protein kinase or calcium/ calmodulin-dependent protein kinases. [10][11][12] One of the remarkable structural features of the benzophenanthridines is their ability to exhibit a pH dependent structural transition between the iminium and alkanolamine forms. It has promising role as an antineoplastic growth inhibitor against various tumor cell lines, such as human breast cancer (MCF-7), human uveal melanoma (OCM-1), human neuroblastoma, colon carcinoma (HCT116) cell lines, and neonatal rat cardiac myocytes.…”

Section: Introductionmentioning

confidence: 99%

Chelerythrine–lysozyme interaction: spectroscopic studies, thermodynamics and molecular modeling exploration

Jash

Basu

Payghan

et al. 2015

Phys. Chem. Chem. Phys.

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The binding of the iminium and alkanolamine forms of chelerythrine to lysozyme (Lyz) was investigated by spectroscopy and docking studies. The thermodynamics of the binding was studied by calorimetry. Spectroscopic evidence suggested that Trp-62 and Trp-63 in the β-domain of the protein are closer to the binding site; moreover, the binding site was at a distance of 2.27 and 2.00 nm from the iminium and alkanolamine forms, respectively, according to the Forster theory of non-radiation energy transfer. The equilibrium binding constants for the iminium and alkanolamine forms at 298 K were evaluated to be 1.29 × 10(5) and 7.79 × 10(5) M(-1), respectively. The binding resulted in an alteration of the secondary structure of the protein with a distinct reduction of the helical organization. The binding of iminium was endothermic, involving electrostatic and hydrophobic interactions, while that of alkanolamine form was exothermic and dominated by hydrogen bonding interactions. Docking studies provided the atomistic details pertaining to the binding of both forms of chelerythrine and supported the higher binding in favour of the alkanolamine over the iminium. Furthermore, molecular dynamics study provided accurate insights regarding the binding of both chelerythrine forms in accordance with the experimental results obtained. Chelerythrine binding pocket involves the catalytic region and aggregation prone K-peptide region, which are sandwiched between one another. Overall, these results suggest that both the forms of the alkaloid bind to the protein but the neutral form has higher affinity than the cationic form.

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Spectroscopic probing of recognition of the G-quadruplex in c-kit promoter by small-molecule natural products

Cited by 33 publications

References 23 publications

Chelerythrine down regulates expression of VEGFA, BCL2 and KRAS by arresting G-Quadruplex structures at their promoter regions

Chelerythrine down regulates expression of VEGFA, BCL2 and KRAS by arresting G-Quadruplex structures at their promoter regions

Plant Alkaloid Chelerythrine Induced Aggregation of Human Telomere Sequence—A Unique Mode of Association between a Small Molecule and a Quadruplex

Chelerythrine–lysozyme interaction: spectroscopic studies, thermodynamics and molecular modeling exploration

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