去铁胺增敏5-艾拉光动力治疗乳腺癌的研究  

Deferoxamine-sensitized 5-Aminolevulinic acid photodynamic therapy for breast cancer

作　　者：王昕钰 刘琦 王守凯 马壮 司丕蕾 Wang Xinyu;Liu Qi;Wang Shoukai;Ma Zhuang;Si Pilei(Academy of Medical Sciences,Zhengzhou University,Zhengzhou 450001,China;Department of Breast Surgery,Henan Provincial People’s Hospital/Zhengzhou University People’s Hospital/Henan University People’s Hospital,Zhengzhou 450003,China)

机构地区：[1]郑州大学医学院,郑州450001 [2]河南省人民医院/郑州大学人民医院/河南大学人民医院乳腺外科,郑州450003

出　　处：《中华实验外科杂志》2024年第4期687-692,共6页Chinese Journal of Experimental Surgery

基　　金：国家自然科学基金青年科学基金项目(82102937);河南省省级科技研发计划联合基金(优势学科培育类)项目(222301420058);河南省中青年卫生健康科技创新杰出青年人才培养项目(YXKC2021026)。

摘　　要：目的探讨在体内外研究去铁胺(DFO)对5-氨基酮戊酸(5-ALA)光动力治疗乳腺癌的增效作用及其机制。方法以实验室传代培养的人乳腺癌细胞MCF-7为模型细胞、雌性BALB/c裸鼠为模型动物,首先使用共聚焦显微镜考察DFO对胞内铁离子水平和对5-ALA在细胞内转化的影响。通过一系列实验考察DFO对光敏剂原卟啉Ⅸ(PpⅨ)的增强转化、细胞凋亡和DNA损伤的增敏作用,最后在动物体内验证DFO增敏5-ALA光动力对MCF-7细胞增殖的抑制作用,组间比较采用t检验。结果5-ALA+DFO组DNA损伤程度较5-ALA组和DFO组严重。DFO显著提高MCF-7细胞中5-ALA的活性中间体PpIX的水平,提高光动力治疗活性氧(ROS)的产生,下调胞内铁离子水平,有效阻断DNA的修复,进而增加对胞内DNA的损伤(拖尾值达到26%,其他组几乎无拖尾)。5-ALA+DFO组的细胞存活率[(58.83±2.41)%]显著低于5-ALA组[(76.17±2.54)%,t=11.06,P<0.01]。5-ALA+DFO组死细胞与活细胞的比值(0.79±0.03)显著高于对照组、5-ALA组和DFO组(0.10±0.02、0.40±0.03、0.28±0.05,t=45.44、22.30、21.83,P<0.01)。5-ALA+DFO组细胞凋亡比例[(26.47±1.42)%]显著高于对照组、5-ALA组和DFO组[(6.65±0.49)%、(12.22±1.03)%、(11.47±0.59)%,t=29.49、17.37、21.83,P<0.01]。DFO可显著降低细胞活力(细胞存活率仅为30%,组间差异P<0.01),显著诱导肿瘤细胞凋亡(凋亡25.8%,组间差异P<0.01),抑制肿瘤细胞的增殖和生长。在裸鼠移植瘤模型中5-ALA+DFO组的肿瘤重量明显低于对照组、5-ALA组和DFO组(对照组的肿瘤较大,平均瘤重3.0 g,而5-ALA+DFO组的肿瘤相对较小,平均瘤重1.9 g)。DFO在体内可有效抑制MCF-7裸鼠移植瘤的增殖,并表现出较低的毒副作用。结论DFO可有效增敏5-ALA的光动力治疗,抑制肿瘤细胞增殖。Objective To study the synergistic effect of deferoxamine(DFO)on 5-Aminolevulinic acid(5-ALA)photodynamic therapy of breast cancer in vivo and in vitro and its mechanism.Methods The laboratory subcultured human breast cancer cell line MCF-7 was used as the model cell,and female BALB/c nude mice were used as the model animals.First,the confocal microscope was used to investigate the effects of DFO on the level of intracellular iron ions and the transformation of 5-ALA in cells.A series of experiments were conducted to investigate the enhanced conversion of photosensitizer protoporphyrinⅨ(PpⅨ),apoptosis,and DNA damage sensitization by DFO.Finally,the inhibitory effect of DFO-enhanced 5-ALA photodynamic therapy on the proliferation of MCF-7 cells was verified in vivo.T-tests was used for comparison between groups.Results The degree of DNA damage in the 5-ALA DFO group was severer than that in the 5-ALA group and the DFO group.DFO significantly increased the level of PpIX,the active intermediate of 5-ALA in MCF-7 cells,increased the production of reactive oxygen species(ROS),down-regulated the level of intracellular iron ions,effectively blocked DNA repair,and then increased the damage to intracellular DNA(tailing value of 26%,and there was almost no tailing in other groups).The cell viability rate of the 5-ALA+DFO group was(58.83±2.41)%,significantly lower than that of the 5-ALA group[(76.17±2.54)%,t=11.06,P<0.01].The ratio of dead cells to live cells in the 5-ALA+DFO group(0.79±0.03)was significantly higher than that in the control group,the 5-ALA group and the DFO group(0.10±0.02,0.40±0.03,0.28±0.05,t=45.44,22.30,21.83,P<0.01).The apoptosis ratio of the 5-ALA+DFO group was(26.47±1.42)%,which was significantly higher than that of the control group,the 5-ALA group,and the DFO group[(6.65±0.49)%,(12.22±1.03)%,(11.47±0.59)%,t=29.49,17.37,21.83,P<0.01).DFO can significantly reduce cell viability(cell survival rate of only 30%,P<0.01),significantly induce apoptosis of tumor cells(apoptosis rate of 25.8%,P<

关 键 词：去铁胺 5-氨基酮戊酸 增敏治疗 乳腺癌 光动力治疗 

分 类 号：R737.9[医药卫生—肿瘤]