| BackgroundGlioma has high invasiveness and poor prognosis in primary brain tumors of the central nervous system.The incidence of gliomas is increasing year by year.The annual growth rate is about 1.2%.It currently accounts for 40%-50%of the incidence of primary intracranial tumors in the adult population.The annual mortality rate of glioma patients in China is more than 30,000.The pathogenesis of gliomas is complex.Although there are many studies on the treatment of gliomas,there are many problems.Therefore,the survival and quality of life of glioma patients have not been significantly improved.Currently,surgical treatment is mainly chemotherapy,radiotherapy,and immunological treatment or Chinese medicine treatment.Among them,chemotherapy is an important method for the treatment of gliomas.In traditional chemotherapeutic drugs,the target of action is mainly directed against substances that cause abnormal proliferation such as DNA,genes,and proteins,or cells that proliferate actively.However,chemotherapeutic drugs often do not specifically kill tumor cells,but also cause damage to normal tissues and organs.Damage;toxic side reactions occur.Although the treatment methods are diversified and individual targeted therapy is available,the prognosis of glioma patients is poor,and there are still problems of short survival time,high recurrence rate,and high mortality rate.Therefore,the treatment of gliomas has so far been still used.It is one of the research hotspots and difficulties for neurosurgeons.Searching new and effective therapeutic technologies brings new hope to patients with gliomas.The chemical structure of Schiff base has a characteristic imine or azomethine characteristic group,ie,its molecular structure(-RC=N-).Schiff base,a new organic compound,has many functions.It is synthesized by a condensation reaction and consists of an amine and a reactive carbonyl group.Schiff base compounds and their metal complexes have been shown to be involved in the treatment of a variety of diseases,including tumor.The nitrogen atom in the Schiffs base structure is a pair of lone pair electrons.Through selective reaction with different amines and aldehydes or ketones with carbonyl groups,various metal ions in the periodic table can be coordinately bound,transition metals and rare earths.Metals form a variety of Schiff base ligands with diverse structure and different properties,such as heterostructure,heteronuclear,mononuclear,polynuclear,and macrocyclic complexes.They can bind DNA to prevent DNA synthesis and cell cycle progression,promote apoptosis,and thus play an anti-tumor effect.Aims1.Synthesis of Schiff base nickel(Ⅱ)complexes 1 and 2 and their structural identification.2.To investigate the effect of Schiff base nickel(Ⅱ)complex on glioma and its mechanism in vivo and in vitro.Methods1.Preparation of Schiff base nickel(Ⅱ)complexes 1 and 2.Structures were determined by single crystal diffractometer.UV-visible absorption spectrometry was employed to observe DNA interactions.2.MTT was used for cell proliferation assay.Analysis of cell colony formation and growth was performed using plate colony formation assays.The effect of apoptosis rate and cell cycle was analyzed by flow cytometry.The mRNA expression of Bcl-2 and Bax was analyzed using real-time quantitative PCR.Caspase 3 activity was measured using the Caspase 3 activity assay kit.3.The nude mice glioma model was prepared by subcutaneous implantation and randomly divided into 3 groups:control group,and Schiff base nickel(Ⅱ)complex 1,2 treatment groups.Each group of tumor-bearing nude mice was examined for body weight and tumor volume.Bcl-2,Bax,and VEGF levels were measured by Western blotting.The Caspase 3 activity assay kit was used to analyze changes in Caspase 3 activity.4.Statistical analysisSPSS 20.0 statistical software was used for satistical analysis to analyze data.Result1.Two novel Schiff-base nickel(Ⅱ)complexes 1 and 2 were successfully prepared and the properties of the two complexes combined with DNA were verified.Two complexes were obtained,named after complexes 1 and 2,respectively.The molecular formula is C28H21C13N4NiO2,C28H21C12NSNiO4.The relative viscosity of the DNA solution was increased as the concentration of the complex increases.Both of them could interact with DNA.2.Both Schiff base nickel(Ⅱ)complexes 1 and 2 could inhibit the proliferation,growth of glioma cell lines and clone formation(P<0.05),promote tumor cell apoptosis,change cell cycle,and increase Bcl-2 expression.The Schiff base nickel complex Ⅱ was more obvious than complex Ⅰ(P<0.01).3.Two complexes could significantly change the body weight of each group of nude mice and have an inhibitory effect on the tumor volume of each group(P<0.05).The expressions of VEGF and Bcl-2 were down-regulated,while Bax expression was increased,and Caspase3 activity was increased.Schiff base nickel(Ⅱ)complex 2 was more pronounced than complex 1(P<0.01).Conclusion1.Two novel Schifif-base nickel(Ⅱ)complexes 1 and 2 have been successfully synthesized in this study.Both of them can interact with DNA by the way of insertion.2.In vitro studies confirmed that Schiff base nickel(Ⅱ)complexes have inhibitory effects on the growth and proliferation of glioma cells.They can alter the cell cycle to induce tumor cells by altering the expression of apoptosis-related genes.The increase of apoptosis exerts an anti-cancer effect,and the Schiff base nickel(Ⅱ)complex 2 acts better than the Schiff base nickel(Ⅱ)complex 1.3.By in vivo studies,Schiff base nickel(Ⅱ)complexes can delay the growth of tumors,improve the quality of life of animal models of glioma,increase the expression of apoptosis-related genes and up-regulate the Caspase3 activity in glioma tissues.Schiff base nickel(Ⅱ)complex 2 acts better than Schiff base nickel(Ⅱ)complex 1. |
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