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

Ghosh, Saptaparni; Jana, Jagannath; Kar, Rup Kumar; Chatterjee, Subhrangsu; Dasgupta, Dipak

doi:10.1021/bi501117x

Cited by 26 publications

(34 citation statements)

References 47 publications

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“…Earlier reports suggested that anticancer activity of Chelerythrine, a naturally occurring benzophenanthridine plant alkaloid is associated with its potential ability to inhibit protein kinese C. It is also reported previously that Chelerythrine is recognized by human telomeric DNA and RNA G-quadruplex3453. In the present study we have shown that Chelerythrine not only binds to human telomeric DNA and RNA G-quadruplex it also binds to quadruplex structures formed in the promoter region of oncogenes like BCL2, VEGFA and KRAS.…”

Section: Discussionsupporting

confidence: 80%

“…The binding constant (K D ) obtained from ITC is closed to other spectroscopic data. The binding affinity (K A ) of Chelerythrine-quadruplex complexes with promoter sequences (BCL2, VEGF and KRAS) is significantly higher than Chelerythrine binding with human telomeric G-quadruplex53. Interestingly the binding affinities are in good agreement with other potent G-quadruplex binders serving as promising anticancer drug targets57.…”

Section: Discussionmentioning

confidence: 86%

“…MD simulation gives the detailed information of complex formation at the atomic level5152. In explicit solvent medium Chelerythrine adjust its position with respect to initial docked state53. The binding ratio obtained from ITC was found to be 1:2 for quadruplex-Chelerythrine complex for all promoter sequences.…”

Section: Resultsmentioning

confidence: 98%

“…The thermodynamic parameters calculated using MMPBSA method, in this context the theoretical results are valuable to be compared with the experimental findings53. The binding energies of quadruplex-Chelerythrine (1:1 and 1:2) complex are shown in Tables S7 and S8.…”

Section: Resultsmentioning

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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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

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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“…On the basis of Nitidine’s reported interactions with G-quadruplexes, 66 we investigated the effect of Nitidine on the three KRAS promoter G-quadruplexes. As previously reported, 28 the Near-G forms an all-parallel G-quadruplex, while the Mid-G and Far-G form mixed parallel/antiparallel G-quadruplexes, with the Far-G being much weaker than the Mid-G, similar to our analyses of the i-motifs.…”

Section: Resultsmentioning

confidence: 99%

Insight into the Complexity of the i-Motif and G-Quadruplex DNA Structures Formed in the KRAS Promoter and Subsequent Drug-Induced Gene Repression

et al. 2017

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Activating KRAS mutations frequently occur in pancreatic, colorectal, and lung adenocarcinomas. While many attempts have been made to target oncogenic KRAS, no clinically useful therapies currently exist. Most efforts to target KRAS have focused on inhibiting the mutant protein; a less explored approach involves targeting KRAS at the transcriptional level. The promoter element of the KRAS gene contains a GC-rich nuclease hypersensitive site with three potential DNA secondary structure-forming regions. These are referred to as the Near-, Mid-, and Far-regions, on the basis of their proximity to the transcription start site. As a result of transcription-induced negative superhelicity, these regions can open up to form unique DNA secondary structures: G-quadruplexes on the G-rich strand and i-motifs on the C-rich strand. While the G-quadruplexes have been well characterized, the i-motifs have not been investigated as thoroughly. Here we show that the i-motif that forms in the C-rich Mid-region is the most stable and exists in a dynamic equilibrium with a hybrid i-motif/hairpin species and an unfolded hairpin species. The transcription factor heterogeneous nuclear ribonucleoprotein K (hnRNP K) was found to bind selectively to the i-motif species and to positively modulate KRAS transcription. Additionally, we identified a benzophenanthridine alkaloid that dissipates the hairpin species and destabilizes the interaction of hnRNP K with the Mid-region i-motif. This same compound stabilizes the three existing KRAS G-quadruplexes. The combined effect of the compound on the Mid-region i-motif and the G-quadruplexes leads to downregulation of KRAS gene expression. This dual i-motif/G-quadruplex-interactive compound presents a new mechanism to modulate gene expression.

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Solution and Solid‐State Analysis of Binding of 13‐Substituted Berberine Analogues to Human Telomeric G‐quadruplexes

Ferraroni

Bazzicalupi

Papi

et al. 2016

Chemistry An Asian Journal

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The interaction between 13-phenylalkyl and 13-diphenylalkyl berberine derivatives (NAX) and human telomeric DNA G4 structures has been investigated by both spectroscopic and crystallographic methods. NAX042 and NAX053 are the best compounds improving the performance of the natural precursor berberine. This finding is in agreement with the X-ray diffraction result for the NAX053-Tel12 adduct, showing the ligand which interacts via π-stacking, sandwiched at the interface of two symmetry-related quadruplex units, with its benzhydryl group contributing to the overall stability of the adduct by means of additional π-stacking interactions with the DNA residues. The berberine derivatives were also investigated for their cytotoxic activity towards a panel of human cancer cell lines. Compounds NAX042 and NAX053 affect the viability of cancer cell lines in a dose-dependent manner.

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

Cited by 26 publications

References 47 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

Insight into the Complexity of the i-Motif and G-Quadruplex DNA Structures Formed in the KRAS Promoter and Subsequent Drug-Induced Gene Repression

Solution and Solid‐State Analysis of Binding of 13‐Substituted Berberine Analogues to Human Telomeric G‐quadruplexes

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