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Study on Mechanism of Tumor Cell Apoptosis Induced by Quercetin Metal Complexes and Interaction of Complexes with DNA

Author: TanJun
Tutor: WangBoChu
School: Chongqing University
Course: Biomedical Engineering
Keywords: Quercetin metal complexes Antitumor DNA binding DNA breaks Computational Chemistry
CLC: O641.4
Type: PhD thesis
Year: 2007
Downloads: 614
Quote: 3
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Abstract


The malignancy has now become one of the main causes of death in the human, looking for anticancer drugs has become a major topic of pharmaceutical research. Recent studies show that some quercetin metal complexes is not only anti-oxidation activity than quercetin, and its inhibition of tumor cell growth is stronger than quercetin. However, quercetin metal complexes antitumor mechanism of action is unclear. Their ability to induce tumor cell apoptosis, signal transduction pathway, target of scientific problems remains to be explored research. The subjects of biochemistry, cell biology, pharmacy, calculated chemistry multidisciplinary means, mainly quercetin metal complexes (Mn, Co, Ni, Cu, Zn) on tumor cell apoptosis, and its DNA binding and catalytic DNA faulting to explore the mechanism of action of quercetin metal complexes induce tumor cell apoptosis and its mechanism of interaction with DNA. The following conclusions: (1) using the MTT assay, fluorescence staining, flow cytometry, and immune cells chemical methods of quercetin metal complexes of anti-tumor activity and induced apoptosis in HepG2 cells, preliminary study quercetin metal complex molecular mechanisms that induce tumor cell apoptosis. 1) The results showed that quercetin metal complexes (Mn, Co, Ni, Cu, Zn) on hepatoma cells HepG2, SMMC-7721, and the growth of A549 cells have significantly inhibited and were dose and The time-dependent manner. Which quercetin manganese, nickel and zinc complexes on tumor cell growth inhibition was significantly stronger than the ligand quercetin, their role in half of the 48 hours in HepG2 cells suppress concentration the the IC 50 were 20.64 of 14.44 and 10.67μmol L -1 , while the the quercetin IC 50 for 33.69μmol L -1 2) morphological observation The results showed that the treatment of HepG2 cells were treated with quercetin manganese, nickel and zinc complexes, chromatin condensation and apoptotic bodies appeared that quercetin manganese, nickel and zinc complexes can induce apoptosis in HepG2 cells. 3) Cell cycle analysis showed that quercetin manganese, nickel and zinc complexes on HepG2 cell growth inhibition may be the cells were arrested in G 0 / G 1 period, so that the DNA synthesis speed is reduced, the cycle of the cell cycle is suppressed achieved. G 0 / G 1 cells were arrested with the induction of apoptosis in HepG2 cells is an important mechanism. The 4) immunocytochemistry results show that the quercetin manganese, nickel and zinc complexes induced HepG2 cells apoptosis by downregulating bcl-2 and survivin in upward of p53 triggered caspase cascade, thereby activating caspase-3 . Knockdown of survivin and bcl-2 expression in HepG2 cells apoptosis induced by quercetin metal complexes both played synergies, but also play a complementary role. (2) by UV spectroscopy, fluorescence spectroscopy and viscosity method quercetin manganese, cobalt, nickel, copper and zinc complexes with calf thymus DNA binding by gel electrophoresis, dehydration malondialdehyde analysis and T4 Connect the experimental systematic study the catalytic quercetin manganese, cobalt, nickel, copper and zinc complexes of plasmid pBR322DNA breakage. Explore the mode of action of quercetin metal complexes and DNA and DNA catalytic fracture mechanism. Found that quercetin metal complexes with nucleic acid enzymes activity. 1) quercetin manganese, cobalt, nickel, and zinc complexes in insert mode only bind to DNA, and quercetin copper complexes with DNA binding mode may be more than one, in addition to the insert mode combined by the electrostatic interaction . DNA, 2) quercetin manganese, cobalt, nickel, copper and zinc complexes can effectively fracture and Quercetin copper complexes of DNA strongest; quercetin manganese, nickel, copper and zinc complexes. The low ionic strength to promote DNA cleavage, the high ionic strength of inhibition of DNA cleavage; ionic strength increases quercetin cobalt complexes can promote the DNA breaks, so quercetin metal complexes of DNA breakage caused by the impact of the ionic strength. 3) If the supercoiled DNA substrate, quercetin manganese, cobalt, nickel, copper and zinc complexes cleave DNA catalyzed reaction comply with the quasi-first-order reaction rate law. The rate constants of 1.18 × 10 -4 s -1 s of of 0.53 × -4 -1 , 0.76 × 10 -4 s -1 , 4.82 × 10 -4 s -1 , 1.68 × 10 -4 s -1 . 4) DNA fragmentation mechanism experiments showed that quercetin manganese, cobalt, nickel, and zinc complexes can DNA breakage proteolytic pathways; quercetin copper complexes to the redox pathway fault DNA may be related to the substance of the Cu (I) OOH. (3) introduction of quantum chemistry and molecular mechanics methods, with the mechanism of antitumor effect and its DNA binding mechanism of quercetin metal theoretical explanation. 1) of quercetin metal complex structure of quantum chemical calculation, through its geometric configuration discussed deformity hexacoordination quercetin metal complexes 6 ligand oxygen atom with the metal ions to form octahedral complexes matter, its coordination structure is reasonable; NBO charge analysis, the frontier molecular orbital analysis and interpretation of coordination complexes, found that the the hydroxyl oxygen coordination ability on the carbonyl oxygen. 2) The results show that the metal complexes of Quercetin LUMO and nearby unoccupied orbital energy than the energy of the DNA nucleotide the HOMO and NHOMO model CG / GC low beneficial complexes accept electrons in the DNA base pairs on enhanced complexes with π-π interaction of DNA base pairs. Quercetin metal complexes antitumor activity and its DNA binding ability LUMO energy brought ligand charge both factors. 3) the use of the molecular mechanics of the insert DNA complexes, the results show that the five quercetin metal complexes can be inserted into the DNA base pairs tend inserted into the minor groove CG / GC base pair. Quercetin metal complexes, complexes with DNA inserted into the ability of theoretical calculation and experimental results on the potential value of the after insert DNA bases. Quercetin metal complexes with DNA binding of the size of the order of zn (Que) 2 gt; Ni (Que) 2 gt; Mn (Que) 2 gt; Co (Que) 2 gt; Cu (Que) 2 . Prompt quercetin metal complexes may inhibit the transcription of GC-rich survivin gene promoter, inhibit survivin expression, thereby promoting tumor cell apoptosis. Quercetin metal, the paper with the material the molecular mechanisms of tumor cell apoptosis induced mechanism of their interaction with DNA exploratory research such compounds to highly efficient, practical chemical nuclease, and anticancer drugs The foundation for the development to provide new ideas for the design of new anticancer drugs.

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CLC: > Mathematical sciences and chemical > Chemistry > Physical Chemistry ( theoretical chemistry ),chemical physics > Structural Chemistry > Complex chemistry ( coordination chemistry )
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