The interaction of telomere DNA G-quadruplex with three bis-benzyltetrahydroisoquinoline alkaloids.

Telomeres are important multifunctional nucleoprotein structures located at the ends of eukaryotic chromosomes. Telomerase regulates telomere elongation, and its activity is associated with tumorigenesis. Because the activity of telomerase can be inhibited by G-quadruplex (G4) formation (a four-stranded DNA with stacks of G-quartets formed by four guanines in a planar structure), the role of G4 in cancer therapy has attracted many research interests. We studied the effects of three natural alkaloids-tetrandrine, fangchinoline, and berbamine-on the stability and formation of telomere DNA G4 with circular dichroism melting spectroscopy (melting-CD), variable temperature ultraviolet (melting-UV), proton nuclear magnetic resonance spectroscopy ((1)H NMR), and molecular docking, and examined the relationships among the alkaloid structure and their activities. We further investigated their cytotoxicity with the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) and flow cytometry (FCM). The results demonstrated that alkaloids increased G4 stability and induced its formation, which added structure diversity of G4-ligands. The results showed that -OH at R(1), -OCH(3) at R(2), and [Formula: see text] at R(3) had higher stability than other substituent groups for these alkaloids. We also found a transition of antiparallel to parallel G4 as the temperature increased. The result indicated the possible advantage of parallel G4 in adversity. In addition, the alkaloids demonstrated a moderate cytotoxicity and proved to be cell cycle blocker in the G(1) phase. These alkaloids have revealed promising potentials to be the agents for antitumor therapy.

[1]  Yalin Tang,et al.  The interaction of telomeric DNA and C-myc22 G-quadruplex with 11 natural alkaloids. , 2012, Nucleic acid therapeutics.

[2]  N. Ip,et al.  Natural products targeting telomere maintenance , 2011 .

[3]  Xiaojie Xu,et al.  Probing the binding affinity of small-molecule natural products to the G-quadruplex in C-myc oncogene by electrospray ionization mass spectrometry. , 2010, Rapid communications in mass spectrometry : RCM.

[4]  T. Efferth,et al.  Chemical-Biology of Natural Products from Medicinal Plants for Cancer Therapy , 2010 .

[5]  Daniela Rhodes,et al.  G-quadruplex structures: in vivo evidence and function. , 2009, Trends in cell biology.

[6]  Lei Zhang,et al.  Berbamine derivatives: a novel class of compounds for anti-leukemia activity. , 2009, European journal of medicinal chemistry.

[7]  Julian Leon Huppert,et al.  Four-stranded DNA: cancer, gene regulation and drug development , 2007, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[8]  R. Xu,et al.  Berbamine selectively induces apoptosis of human acute promyelocytic leukemia cells via survivin-mediated pathway. , 2007, Chinese medical journal.

[9]  R. Gartenhaus,et al.  Telomere uncapping by the G-quadruplex ligand RHPS4 inhibits clonogenic tumour cell growth in vitro and in vivo consistent with a cancer stem cell targeting mechanism , 2007, British Journal of Cancer.

[10]  R. Xu,et al.  Berbamine induces apoptosis in human hepatoma cell line SMMC7721 by loss in mitochondrial transmembrane potential and caspase activation , 2007, Journal of Zhejiang University SCIENCE B.

[11]  N. Maizels,et al.  Dynamic roles for G4 DNA in the biology of eukaryotic cells , 2006, Nature Structural &Molecular Biology.

[12]  A. Phan,et al.  Different loop arrangements of intramolecular human telomeric (3+1) G-quadruplexes in K+ solution , 2006, Nucleic acids research.

[13]  Yan Xu,et al.  The new models of the human telomere d[AGGG(TTAGGG)3] in K+ solution. , 2006, Bioorganic & medicinal chemistry.

[14]  N. Maizels,et al.  Gene function correlates with potential for G4 DNA formation in the human genome , 2006, Nucleic acids research.

[15]  Dinshaw J. Patel,et al.  Structure of the human telomere in K+ solution: an intramolecular (3 + 1) G-quadruplex scaffold. , 2006, Journal of the American Chemical Society.

[16]  Mao-fang Lin,et al.  [Effects of berbamine on K562 cells and its mechanisms in vitro and in vivo]. , 2005, Zhongguo shi yan xue ye xue za zhi.

[17]  S. Neidle,et al.  Highly prevalent putative quadruplex sequence motifs in human DNA , 2005, Nucleic acids research.

[18]  W. Seow,et al.  Comparative effects of tetrandrine and berbamine on subcutaneous air pouch inflammation induced by interleukin-1, tumour necrosis factor and platelet-activating factor , 1992, Agents and Actions.

[19]  Jianguo Cao,et al.  Multidrug resistance reversal in human gastric carcinoma cells by neferine. , 2004, World journal of gastroenterology.

[20]  Jianhui Liu,et al.  Effects of triethylene tetraamine on telomerase activity and proliferation in HeLa cells , 2004, Cell biology international.

[21]  N. Sugimoto,et al.  Duplex dissociation of telomere DNAs induced by molecular crowding. , 2004, Journal of the American Chemical Society.

[22]  A. Phan,et al.  Two-repeat human telomeric d(TAGGGTTAGGGT) sequence forms interconverting parallel and antiparallel G-quadruplexes in solution: distinct topologies, thermodynamic properties, and folding/unfolding kinetics. , 2003, Journal of the American Chemical Society.

[23]  Jianhui Liu,et al.  Triethylene tetraamine: a novel telomerase inhibitor. , 2003, Bioorganic & medicinal chemistry letters.

[24]  Chun-ching Lin,et al.  Tetrandrine-induced cell cycle arrest and apoptosis in Hep G2 cells. , 2003, Life sciences.

[25]  P. Bates,et al.  Biophysical and biological properties of quadruplex oligodeoxyribonucleotides. , 2003, Nucleic acids research.

[26]  S. Bombard,et al.  Platinum cross-linking of adenines and guanines on the quadruplex structures of the AG3(T2AG3)3 and (T2AG3)4 human telomere sequences in Na+ and K+ solutions. , 2003, Nucleic acids research.

[27]  Stephen Neidle,et al.  Structure of a G-quadruplex-ligand complex. , 2003, Journal of molecular biology.

[28]  Yu-Jen Chen.  Potential role of tetrandrine in cancer therapy. , 2002, Acta pharmacologica Sinica.

[29]  J. Harper,et al.  Coupling of DNA Synthesis and Histone Synthesis in S Phase Independent of Cyclin/cdk2 Activity , 2002, Molecular and Cellular Biology.

[30]  I. Kang,et al.  Tetrandrine cytotoxicity and its dual effect on oxidative stress-induced apoptosis through modulating cellular redox states in Neuro 2a mouse neuroblastoma cells. , 2002, Life sciences.

[31]  Z. Ji,et al.  Inhibition of telomerase activity and bcl-2 expression in berbamine-induced apoptosis in HL-60 cells. , 2002, Planta medica.

[32]  L. Hurley,et al.  G-quadruplex DNA: a potential target for anti-cancer drug design. , 2000, Trends in pharmacological sciences.

[33]  M. Chung,et al.  Anti-inflammatory effects of fangchinoline and tetrandrine. , 2000, Journal of ethnopharmacology.

[34]  P. Bates,et al.  Antiproliferative Activity of G-rich Oligonucleotides Correlates with Protein Binding* , 1999, The Journal of Biological Chemistry.

[35]  E. Raymond,et al.  Effects of cationic porphyrins as G-quadruplex interactive agents in human tumor cells. , 1999, Cancer research.

[36]  Jean-Louis Mergny,et al.  Following G‐quartet formation by UV‐spectroscopy , 1998, FEBS letters.

[37]  J. Shay,et al.  Normal human chromosomes have long G-rich telomeric overhangs at one end. , 1997, Genes & development.

[38]  T R Hughes,et al.  Reverse transcriptase motifs in the catalytic subunit of telomerase. , 1997, Science.

[39]  J. Ladbury,et al.  Molecular anchoring of duplex and triplex DNA by disubstituted anthracene-9,10-diones: Calorimetric, UV melting, and competition dialysis studies , 1996 .

[40]  K. Riabowol,et al.  Selective inhibition of telomerase activity during terminal differentiation of immortal cell lines. , 1996, Cancer research.

[41]  M. Mandal,et al.  Cell cycle-dependent modulation of telomerase activity in tumor cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[42]  S. Neidle,et al.  A molecular anchor for stabilizing triple-helical DNA. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[43]  James M. Roberts,et al.  Negative regulation of G1 in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-beta. , 1993, Science.

[44]  N. Kallenbach,et al.  Thermodynamics of G-tetraplex formation by telomeric DNAs. , 1993, Biochemistry.

[45]  M. Bansal,et al.  Hairpin and parallel quartet structures for telomeric sequences. , 1992, Nucleic acids research.

[46]  W. Bonner,et al.  Separation of basal histone synthesis from S-phase histone synthesis in dividing cells , 1981, Cell.

[47]  J. Smith,et al.  Do cells cycle? , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[48]  I. Cameron,et al.  EVIDENCE FOR AN ESSENTIALLY CONSTANT DURATION OF DNA SYNTHESIS IN RENEWING EPITHELIA OF THE ADULT MOUSE , 1963, The Journal of cell biology.

[49]  D. Davies,et al.  Helix formation by guanylic acid. , 1962, Proceedings of the National Academy of Sciences of the United States of America.