Berberine, the most known quaternary protoberberine alkaloid (QPA), has been reported to inhibit the SIK3 protein connected with breast cancer. Berberine also appears to reduce the bcl-2 and XIAP expression-proteins responsible for the inhibition of apoptosis. As some problems in the therapy with berberine arose, we studied the DNA binding properties of escholidine, another QPA alkaloid. CD, fluorescence, and NMR examined models of i-motif and G-quadruplex sequences present in the n-myc gene and the c-kit gene. We provide evidence that escholidine does not induce stabilization of the i-motif sequences, while the interaction with G-quadruplex structures appears to be more significant.

Department of Biochemistry Faculty of Medicine Masaryk University Kamenice 5 62500 Brno Czech Republic

Department of Chemical Engineering and Analytical Chemistry University of Barcelona Marti i Franquès 1 E 08028 Barcelona Spain

Department of Chemistry Faculty of Science Masaryk University Kamenice 5 62500 Brno Czech Republic

Department of Food Environmental and Nutritional Sciences Section of Chemical and Biomolecular Sciences University of Milan Via Celoria 2 20133 Milan Italy

Scientia Advice di Roberto Artali 20832 Desio Italy

Zobrazit více v PubMed

Rajecky M., Slaninova I., Mokrisova P., Urbanova J., Palkovsky M., Taborska E., Taborsky P. Alkaloid chelirubine and DNA: Blue and red luminescence. Talanta. 2013;105:317–319. doi: 10.1016/j.talanta.2012.10.045. PubMed DOI

Rybakova S., Rajecky M., Urbanova J., Pencikova K., Taborska E., Gargallo R., Taborsky P. Interaction of oligonucleotides with benzo c phenanthridine alkaloid sanguilutine. Chem. Pap. 2013;67:568–572. doi: 10.2478/s11696-013-0340-x. DOI

Sandor R., Slanina J., Midlik A., Sebrlova K., Novotna L., Carnecka M., Slaninova I., Taborsky P., Taborska E., Pes O. Sanguinarine is reduced by NADH through a covalent adduct. Phytochemistry. 2018;145:77–84. doi: 10.1016/j.phytochem.2017.10.010. PubMed DOI

Rajecky M., Sebrlova K., Mravec F., Taborsky P. Influence of Solvent Polarity and DNA-Binding on Spectral Properties of Quaternary Benzo c phenanthridine Alkaloids. PLoS ONE. 2015;10:e0129925. doi: 10.1371/journal.pone.0129925. PubMed DOI PMC

Leitao da-Cunha E.V., Fechine I.M., Guedes D.N., Barbosa-Filho J.M., Sobral da Silva M. Protoberberine Alkaloids. In: Cordell G.A., editor. The Alkaloids: Chemistry and Biology. Volume 62. Academic Press; Cambridge, MA, USA: 2005. pp. 1–75. PubMed

Grycová L., Dostál J., Marek R. Quarternary Protoberberine Alkaloids. Volume 68. Elsevier; Amsterdam, The Netherlands: 2007. pp. 150–175. PubMed

Dostál J., Slavík J. Novější Poznatky o Sanguinarinu a Příbuzných Alkaloidech. Chemické Listy; Praha, Czech Republic: 2000. pp. 15–20.

Majidzadeh H., Araj-Khodaei M., Ghaffari M., Torbati M., Ezzati Nazhad Dolatabadi J., Hamblin M.R. Nano-based delivery systems for berberine: A modern anti-cancer herbal medicine. Colloids Surf. B Biointerfaces. 2020;194:111188. doi: 10.1016/j.colsurfb.2020.111188. PubMed DOI

Ponnusamy L., Kothandan G., Manoharan R. Berberine and Emodin abrogates breast cancer growth and facilitates apoptosis through inactivation of SIK3-induced mTOR and Akt signaling pathway. Biochim. Biophys. Acta (BBA)—Mol. Basis Dis. 2020;1866:165897. doi: 10.1016/j.bbadis.2020.165897. PubMed DOI

Ma W., Zhang Y., Yu M., Wang B., Xu S., Zhang J., Li X., Ye X. In-vitro and in-vivo anti-breast cancer activity of synergistic effect of berberine and exercise through promoting the apoptosis and immunomodulatory effects. Int. Immunopharmacol. 2020;87:106787. doi: 10.1016/j.intimp.2020.106787. PubMed DOI

Gu S., Song X., Xie R., Ouyang C., Xie L., Li Q., Su T., Xu M., Xu T., Huang D., et al. Berberine inhibits cancer cells growth by suppressing fatty acid synthesis and biogenesis of extracellular vesicles. Life Sci. 2020;257:118122. doi: 10.1016/j.lfs.2020.118122. PubMed DOI

Chudík S., Marek R., Seckárová P., Necas M., Dostál J., Slavík J. Revision of the structure of escholidine. J. Nat. Prod. 2006;69:954–956. doi: 10.1021/np060078e. PubMed DOI

Slavík J., Dolejš L., Sedmera P. Alkaloids of the Papaveraceae, XLIV. Quaternary alkaloids from roots of three Escholtzia species and from the aerial part of Hunnemannia fumariaefolia SWEET: Constitution of escholidine. Collect. Czechoslov. Chem. Commun. 1970;35:2597–2612. doi: 10.1135/cccc19702597. DOI

Schäfer H.L., Schäfer H., Schneider W., Elstner E.F. Sedative action of extract combinations of Eschscholtzia californica and Corydalis cava. Arzneim.-Forsch. 1995;45:124–126. PubMed

Rolland A., Fleurentin J., Lanhers M.C., Younos C., Misslin R., Mortier F., Pelt J.M. Behavioural effects of the American traditional plant Eschscholzia californica: Sedative and anxiolytic properties. Planta Med. 1991;57:212–216. doi: 10.1055/s-2006-960076. PubMed DOI

Jain L., Tripathi M., Pandey V.B. Alkaloids of Eschscholtzia californica. Planta Med. 1996;62:188. doi: 10.1055/s-2006-957856. PubMed DOI

Bochman M.L., Paeschke K., Zakian V.A. DNA secondary structures: Stability and function of G-quadruplex structures. Nat. Rev. Genet. 2012;13:770–780. doi: 10.1038/nrg3296. PubMed DOI PMC

Takahashi S., Sugimoto N. Quantitative Analysis of Stall of Replicating DNA Polymerase by G-Quadruplex Formation. In: Yang D., Lin C., editors. G-Quadruplex Nucleic Acids: Methods and Protocols. Springer; New York, NY, USA: 2019. pp. 257–274. PubMed

Abou Assi H., Garavís M., González C., Damha M.J. i-Motif DNA: Structural features and significance to cell biology. Nucleic Acids Res. 2018;46:8038–8056. doi: 10.1093/nar/gky735. PubMed DOI PMC

Spiegel J., Adhikari S., Balasubramanian S. The Structure and Function of DNA G-Quadruplexes. Trends Chem. 2020;2:123–136. doi: 10.1016/j.trechm.2019.07.002. PubMed DOI PMC

Blackburn G.M. Nucleic Acids in Chemistry and Biology. 3rd ed. Royal Society of Chemistry; Cambridge, UK: 2006.

Khandelwal P., Panchal S.C., Radha P.K., Hosur R.V. Solution structure and dynamics of GCN4 cognate DNA: NMR investigations. Nucleic Acids Res. 2001;29:499–505. doi: 10.1093/nar/29.2.499. PubMed DOI PMC

Phan A.T., Mergny J.L. Human telomeric DNA: G-quadruplex, i-motif and watson-crick double helix. Nucleic Acids Res. 2002;30:4618–4625. doi: 10.1093/nar/gkf597. PubMed DOI PMC

Neidle S. Principles of Nucleic Acid Structure. Academic Press; New York, NY, USA: 2008. 2—The Building-Blocks of DNA and RNA; pp. 20–37.

Burge S., Parkinson G.N., Hazel P., Todd A.K., Neidle S. Quadruplex DNA: Sequence, topology and structure. Nucleic Acids Res. 2006;34:5402–5415. doi: 10.1093/nar/gkl655. PubMed DOI PMC

Vojtylová T., Dospivová D., Třísková O., Pilařová I., Lubal P., Farková M., Trnková L., Táborský P. Spectroscopic study of protonation of oligonucleotides containing adenine and cytosine. Chem. Pap. 2009;63:731–737. doi: 10.2478/s11696-009-0077-8. DOI

Dzatko S., Krafcikova M., Hänsel-Hertsch R., Fessl T., Fiala R., Loja T., Krafcik D., Mergny J.-L., Foldynova-Trantirkova S., Trantirek L. Evaluation of the Stability of DNA i-Motifs in the Nuclei of Living Mammalian Cells. Angew. Chem. Int. Ed. 2018;57:2165–2169. doi: 10.1002/anie.201712284. PubMed DOI PMC

Alba J.J., Sadurní A., Gargallo R. Nucleic Acid i-Motif Structures in Analytical Chemistry. Crit. Rev. Anal. Chem. 2016;46:443–454. doi: 10.1080/10408347.2016.1143347. PubMed DOI

Jin K.S., Shin S.R., Ahn B., Rho Y., Kim S.J., Ree M. pH-Dependent Structures of an i-Motif DNA in Solution. J. Phys. Chem. B. 2009;113:1852–1856. doi: 10.1021/jp808186z. PubMed DOI

Wright E.P., Huppert J.L., Waller Z.A.E. Identification of multiple genomic DNA sequences which form i-motif structures at neutral pH. Nucleic Acids Res. 2017;45:2951–2959. doi: 10.1093/nar/gkx090. PubMed DOI PMC

Gurung S.P., Schwarz C., Hall J.P., Cardin C.J., Brazier J.A. The importance of loop length on the stability of i-motif structures. Chem. Commun. 2015;51:5630–5632. doi: 10.1039/C4CC07279K. PubMed DOI PMC

Brooks T.A., Kendrick S., Hurley L. Making sense of G-quadruplex and i-motif functions in oncogene promoters. FEBS J. 2010;277:3459–3469. doi: 10.1111/j.1742-4658.2010.07759.x. PubMed DOI PMC

Leroy J.-L., Guéron M., Mergny J.-L., Hélène C. Intramolecular folding of a fragment of the cytosine-rich strand of telomeric DNA into an i-motif. Nucleic Acids Res. 1994;22:1600–1606. doi: 10.1093/nar/22.9.1600. PubMed DOI PMC

Khan N., Aviñó A., Tauler R., González C., Eritja R., Gargallo R. Solution equilibria of the i-motif-forming region upstream of the B-cell lymphoma-2 P1 promoter. Biochimie. 2007;89:1562–1572. doi: 10.1016/j.biochi.2007.07.026. PubMed DOI

Simonsson T., Pribylova M., Vorlickova M. A Nuclease Hypersensitive Element in the Human c-myc Promoter Adopts Several Distinct i-Tetraplex Structures. Biochem. Biophys. Res. Commun. 2000;278:158–166. doi: 10.1006/bbrc.2000.3783. PubMed DOI

Brazier J.A., Shah A., Brown G.D. I-Motif formation in gene promoters: Unusually stable formation in sequences complementary to known G-quadruplexes. Chem. Commun. 2012;48:10739–10741. doi: 10.1039/c2cc30863k. PubMed DOI

Zeraati M., Langley D.B., Schofield P., Moye A.L., Rouet R., Hughes W.E., Bryan T.M., Dinger M.E., Christ D. I-motif DNA structures are formed in the nuclei of human cells. Nat. Chem. 2018;10:631–637. doi: 10.1038/s41557-018-0046-3. PubMed DOI

Feng L., Dong Z., Tao D., Zhang Y., Liu Z. The acidic tumor microenvironment: A target for smart cancer nano-theranostics. Nat. Sci. Rev. 2018;5:269–286. doi: 10.1093/nsr/nwx062. DOI

Jarosova P., Sandor R., Slaninkova A., Vido M., Pes O., Taborsky P. Quaternary protoberberine alkaloids and their interactions with DNA. Chem. Pap. 2019;73:2965–2973. doi: 10.1007/s11696-019-00857-z. DOI

Jarosova P., Paroulek P., Rajecky M., Rajecka V., Taborska E., Eritja R., Aviñó A., Mazzini S., Gargallo R., Taborsky P. Naturally occurring quaternary benzo[c]phenanthridine alkaloids selectively stabilize G-quadruplexes. Pchys. Chem. Chem. Phys. 2018;20:21772–21782. doi: 10.1039/C8CP02681E. PubMed DOI

Adamcik J., Valle F., Witz G., Rechendorff K., Dietler G. The promotion of secondary structures in single-stranded DNA by drugs that bind to duplex DNA: An atomic force microscopy study. Nanotechnology. 2008;19:384016. doi: 10.1088/0957-4484/19/38/384016. PubMed DOI

Wright E.P., Day H.A., Ibrahim A.M., Kumar J., Boswell L.J.E., Huguin C., Stevenson C.E.M., Pors K., Waller Z.A.E. Mitoxantrone and Analogues Bind and Stabilize i-Motif Forming DNA Sequences. Sci. Rep. 2016;6:39456. doi: 10.1038/srep39456. PubMed DOI PMC

Mazzini S., Bellucci M.C., Mondelli R. Mode of binding of the cytotoxic alkaloid berberine with the double helix oligonucleotide d(AAGAATTCTT)2. Bioorganic Med. Chem. 2003;11:505–514. doi: 10.1016/S0968-0896(02)00466-2. PubMed DOI

Gargallo R., Aviñó A., Eritja R., Jarosova P., Mazzini S., Scaglioni L., Taborsky P. Study of alkaloid berberine and its interaction with the human telomeric i-motif DNA structure. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2021;248:119185. doi: 10.1016/j.saa.2020.119185. PubMed DOI

Fernando H., Reszka A.P., Huppert J., Ladame S., Rankin S., Venkitaraman A.R., Neidle S., Balasubramanian S. A Conserved Quadruplex Motif Located in a Transcription Activation Site of the Human c-kit Oncogene. Biochemistry. 2006;45:7854–7860. doi: 10.1021/bi0601510. PubMed DOI PMC

Kuryavyi V., Majumdar A., Shallop A., Chernichenko N., Skripkin E., Jones R., Patel D.J. A double chain reversal loop and two diagonal loops define the architecture of unimolecular DNA quadruplex containing a pair of stacked G(syn)·G(syn)·G(anti)·G(anti) tetrads flanked by a G·(T-T) triad and a T·T·T triple1. J. Mol. Biol. 2001;310:181–194. doi: 10.1006/jmbi.2001.4759. PubMed DOI

Benabou S., Ferreira R., Aviñó A., González C., Lyonnais S., Solà M., Eritja R., Jaumot J., Gargallo R. Solution equilibria of cytosine- and guanine-rich sequences near the promoter region of the n-myc gene that contain stable hairpins within lateral loops. Biochim. Biophys. Acta (BBA)—Gen. Subj. 2014;1840:41–52. doi: 10.1016/j.bbagen.2013.08.028. PubMed DOI

Bell E., Chen L., Liu T., Marshall G.M., Lunec J., Tweddle D.A. MYCN oncoprotein targets and their therapeutic potential. Cancer Lett. 2010;293:144–157. doi: 10.1016/j.canlet.2010.01.015. PubMed DOI

Mergny J.-L., Riou J.-F., Mailliet P., Teulade-Fichou M.-P., Gilson E. Natural and pharmacological regulation of telomerase. Nucleic Acids Res. 2002;30:839–865. doi: 10.1093/nar/30.4.839. PubMed DOI PMC

Datta B., Armitage B.A. Hybridization of PNA to Structured DNA Targets:  Quadruplex Invasion and the Overhang Effect. J. Am. Chem. Soc. 2001;123:9612–9619. doi: 10.1021/ja016204c. PubMed DOI

Puglisi J.D., Tinoco I. Absorbency melting curves of RNA. Methods Enzymol. 1989;180:304–325. PubMed

Breslauer K.J. Extracting thermodynamic data from equilibrium melting curves for oligonucleotide order-disorder transitions. Energetics Biol. Macromol. 1995;259:221–242. PubMed

Dyson R.M., Kaderli S., Lawrance G.A., Maeder M. Second order global analysis: The evaluation of series of spectrophotometric titrations for improved determination of equilibrium constants. Anal. Chim. Acta. 1997;353:381–393. doi: 10.1016/S0003-2670(97)87800-2. DOI

Kuryavyi V., Phan A.T., Patel D.J. Solution structures of all parallel-stranded monomeric and dimeric G-quadruplex scaffolds of the human c-kit2 promoter. Nucleic Acids Res. 2010;38:6757–6773. doi: 10.1093/nar/gkq558. PubMed DOI PMC

Moraca F., Amato J., Ortuso F., Artese A., Pagano B., Novellino E., Alcaro S., Parrinello M., Limongelli V. Ligand binding to telomeric G-quadruplex DNA investigated by funnel-metadynamics simulations. Proc. Natl. Acad. Sci. USA. 2017;114:E2136–E2145. doi: 10.1073/pnas.1612627114. PubMed DOI PMC

Morris G.M., Goodsell D.S., Halliday R.S., Huey R., Hart W.E., Belew R.K., Olson A.J. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J. Comput. Chem. 1998;19:1639–1662. doi: 10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B. DOI

Morris G.M., Huey R., Lindstrom W., Sanner M.F., Belew R.K., Goodsell D.S., Olson A.J. AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. J. Comput. Chem. 2009;30:2785–2791. doi: 10.1002/jcc.21256. PubMed DOI PMC

Gasteiger J., Marsili M. Iterative Partial Equalization of Orbital Electronegativity—A Rapid Access to Atomic Charges. Tetrahedron. 1980;36:3219–3228. doi: 10.1016/0040-4020(80)80168-2. DOI

Sanner M.F. Python: A programming language for software integration and development. J. Mol. Graph. Model. 1999;17:57–61. PubMed

Goddard T.D., Huang C.C., Meng E.C., Pettersen E.F., Couch G.S., Morris J.H., Ferrin T.E. UCSF ChimeraX: Meeting modern challenges in visualization and analysis. Protein Sci. 2018;27:14–25. doi: 10.1002/pro.3235. PubMed DOI PMC

Ambrus A., Chen D., Dai J., Bialis T., Jones R.A., Yang D. Human telomeric sequence forms a hybrid-type intramolecular G-quadruplex structure with mixed parallel/antiparallel strands in potassium solution. Nucleic Acids Res. 2006;34:2723–2735. doi: 10.1093/nar/gkl348. PubMed DOI PMC

Benabou S., Aviñó A., Lyonnais S., González C., Eritja R., De Juan A., Gargallo R. i-motif structures in long cytosine-rich sequences found upstream of the promoter region of the SMARCA4 gene. Biochimie. 2017;140:20–33. doi: 10.1016/j.biochi.2017.06.005. PubMed DOI

Kim S., Chen J., Cheng T.J., Gindulyte A., He J., He S.Q., Li Q.L., Shoemaker B.A., Thiessen P.A., Yu B., et al. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res. 2021;49:D1388–D1395. doi: 10.1093/nar/gkaa971. PubMed DOI PMC