Copper, iron, zinc-fluorouracil complexes synthesized in vitro inhibit tumor cell proliferation

doi:10.3969/j.issn.2095-4344.2014.39.014

Abstract

Abstract:

BACKGROUND: Anticancer drug and organic metal complexes will form a new structure or a change in ion concentration, thus changing both the activity and toxicity to produce a synergistic effect.

OBJECTIVE: To synthesize new high-efficient and low-toxic metal-fluorouracil complexes as anticancer drugs.

METHODS: Copper, zinc and iron salts and fluorouracil were used to synthesize four copper, zinc and iron-fluorouracil complexes that were [Cu(5-Fu)₂Cl₂], [Cu(5-Fu)₂(NO₃)₂], [Fe(5-Fu)₃]SO₄ and [Zn(5-Fu)₂Cl₂]. Preliminary chemical structures of the four complexes were confirmed by elemental analysis and mass spectrometry. Their inhibitory activity on human cancer cells, human leukemia cell line K562 and human colon cancer cell line HCT-116, was measured by MTT colorimetric assay.

RESULTS AND CONCLUSION: [Cu(5-Fu)₂Cl₂], [Cu(5-Fu)₂(NO₃)₂], [Zn(5-Fu)₂Cl₂] and [Fe(5-Fu)₃SO₄] were successfully synthesized. These four complexes at a mass concentration of 0.1-100 mg/L inhibited the proliferation of K562 and HCT-116 to different extents. The IC₅₀ values of these four complexes on K562 and HCT-116 cells were lower than those of fluorouracil, and their cytotoxicity was 1.5-7.8 times higher than that of fluorouracil. To conclude, copper/iron/zinc-fluorouracil complexes exhibit synergic inhibitory effects on cancer cell proliferation.

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

全文链接：

Key words: fluorouracil, cell line, tumor, cell proliferation

CLC Number:

R318

Zhou Yi-ping, Chen Yuan-xiao, Zhou Yun, Shi Zhong-zheng, Luo Min, Zhong Wen-yuan, Chen Ying-jie. Copper, iron, zinc-fluorouracil complexes synthesized in vitro inhibit tumor cell proliferation[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(39): 6309-6315.

Figures/Tables 4

2.2 配合物的体外抗肿瘤活性对K562、HCT-116细胞的增殖抑制作用：铜、铁、锌盐及氟尿嘧啶配体，以及由它们形成的铜、铁、锌-氟尿嘧啶配合物在体外对K562，HCT-116细胞的增殖抑制作用见图2所示。图2A-D显示的是以铜盐CuCl2•2H2O， Cu(NO3)2•3H2O为配体的作用情况，在0.1-100 mg/L范围内，2种铜盐均能较强地抑制2株细胞的增殖，在 0.1-30 mg/L范围内，作用随浓度的增强而增强；在 30-100 mg/L范围内，作用持平，呈现平台期。与5-氟尿嘧啶形成配合物[Cu(5-Fu)2Cl2]和[Cu(5-Fu)2(NO3)2]后，配合物对2株细胞的增殖抑制作用较2种铜盐降低，在 1-10 mg/L范围内，作用较氟尿嘧啶增强。经计算，[Cu(5-Fu)2Cl2]和[Cu(5-Fu)2(NO3)2]对K562细胞的IC50值(表2)分别为88 μmol/L和54 μmol/L，细胞毒活性是氟尿嘧啶(表2，IC50=200 μmol/L)的2.3倍和3.7倍；对HCT-116细胞的IC50值分别为120 μmol/L和79 μmol/L，细胞毒活性是氟尿嘧啶(表2，IC50=180 μmol/L)的1.5倍和2.3倍。图2E，F显示的是以锌盐ZnCl2•2H2O为配体的作用情况，在0.1-100 mg/L范围内，ZnCl2•2H2O能较强抑制2株细胞的增殖，在0.1-30 mg/L范围内，作用随浓度的增强而增强；在30-100 mg/L范围内，作用持平或缓慢增强，呈现平台期。与氟尿嘧啶形成配合物[Zn(5-Fu)2Cl2]后，在0.1-10 mg/L范围内，配合物对2株细胞的增殖抑制作用较ZnCl2•2H2O增强，在0.1-30 mg/L范围内，作用较氟尿嘧啶增强。经计算，[Zn(5-Fu)2Cl2] 对K562细胞的IC50值(表2)为54 μmol/L，细胞毒活性是氟尿嘧啶(表2，IC50= 200 μmol/L)的3.7倍；对HCT-116细胞的IC50值为23 μmol/L，细胞毒活性是氟尿嘧啶(表2，IC50=180 μmol/L)的7.8倍。图2G，H显示的是以铁盐FeSO4•7H2O为配体的作用情况，在0.1-100 mg/L范围内，FeSO4•7H2O能够促进K562和HCT-116细胞的增殖，在1-10 mg/L范围内，作用随浓度的增强而增强；在10-100 mg/L范围内，作用基本持平，呈现平台期。与氟尿嘧啶形成配合物[Fe(5-Fu)3]SO4后，则对2株细胞均呈现增殖抑制作用。在1-10 mg/L范围内，配合物对K562细胞的增殖抑制作用较氟尿嘧啶增强；在0.1-30 mg/L范围内，配合物对HCT-116细胞的增殖抑制作用较氟尿嘧啶增强。经计算，[Fe(5-Fu)3]SO4对K562细胞的IC50值(表2)为87 μmol/L，细胞毒活性是氟尿嘧啶(表2，IC50=200 μmol/L)的2.3倍；对HCT-116细胞的IC50值为 33 μmol/L，细胞毒活性是氟尿嘧啶(表2，IC50=180 μmol/L)的5.5倍。 "

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