松花粉多糖硫酸酯化前后对白血病细胞的作用研究
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摘要
本实验室体内研究曾表明,马尾松硫酸酯化多糖(SPPM60)能抑制HepG2细胞增殖,并诱导HepG2细胞分化,逆转其恶性,而PPM60无明显作用。本次实验拟以人白血病细胞株K562细胞为研究对象,考察PPM60或SPPM60对其生长状态的影响并对其机理进行初步探讨,以期为马尾松花粉多糖的开发利用提供理论支持,并为白血病的防治提供一种潜在的方法。实验主要分为以下几个部分:
一、PPM60的分离纯化及硫酸酯化修饰:采用氯磺酸-吡啶法分别对50mg PPM60-A、PPM60-B、PPM60-C、PPM60-D进行硫酸酯化改性,得到暗黄色产物SPPM60-A、SPPM60-B、SPPM60-C、SPPM60-D61.8mg、79.0mg、63.2mg、71.9mg。用氯化钡-明胶比浊法鉴定其硫酸根含量并计算取代度分别为1.28、1.63、1.31、1.49。
二、PPM60硫酸酯化前后对K562细胞增殖能力及细胞周期的影响:MTT法检测发现PPM60对K562细胞的增殖的抑制作用明显强于SPPM60,400μg/mLPPM60或SPPM60作用K562细胞48h时抑制率分别约达到32%和16%。瑞氏染色、Ho.33342/PI荧光双染观察PPM60或SPPM60对K562细胞形态的影响。经400μg/mLPPM60作用48h后,细胞体积缩小,核直径减小,核染色质浓缩,胞质丰富,核浆比例降低,细胞膜完整但不光滑,并出现一定程度的凋亡;SPPM60组与对照组相比没有明显差别。流式细胞技术检测PPM60或SPPM60处理前后K562细胞周期分布的变化。PPM60组较对照组G0/G1期细胞比例显著性增加,细胞周期发生了G0/G1期阻滞,并诱导凋亡发生。SPPM60处理组细胞细胞周期各个时相以及凋亡率与对照组相比,均没有显著性差异。
三、PPM60硫酸酯化前后对K562细胞[Ca2+]i和活性氧的影响:分别以Fura-2/AM和DCFH/DA为探针,荧光分光光度计检测PPM60或SPPM60处理前后[Ca2+]i和胞内ROS的变化。PPM60作用24h、48h、72h后,PPM60组[Ca2+]i与对照组相比均明显上升,SPPM60组[Ca2+]i与对照组各时间点均显著性降低;PPM60组胞内ROS水平明显升高,SPPM60组胞内ROS水平与对照组相比基本没有变化。黄嘌呤氧化酶法测定超氧化物歧化酶(SOD)活力法检测PPM60或SPPM60处理前后胞内SOD水平的变化。72h内K562细胞PPM60作用组的SOD活力较对照组有下降趋势;而SPPM60组胞内SOD活力与对照组相比,基本没有变化。TBA法检测PPM60或SPPM60处理前后胞内丙二醛(MDA)水平的变化。12h、24h、48h、72h后,PPM60组细胞内MDA与对照组相比都有所增加,SPPM60组胞内MDA水平高于对照组,但幅度甚小。
以上结果表明:(1)PPM60对K562细胞有较强的抑制作用,硫酸酯化修饰之后降低了其抑制作用。(2)PPM60抑制K562细胞的机制可能是升高细胞内钙离子和活性氧浓度,阻滞细胞周期于G0/G1期,并诱导K562细胞产生凋亡。
The anticancer research of polysaccharides from Pinus massoniana pollen(PPM60) and its sulfated derivative(SPPM60)has indicated that, SPPM60 inhibited the growth of human HepG2 cells in vitro,prevent cell cycle, inhibit cell proliferation and growth;PPM60 had no inhibitory effect on HepG2 cells growth. This research aims to determine the effects of PPM60 and SPPM60 on the proliferation and differentiation of human K562 cells, and then to give some theoretical and experimental roof for the research of SPPM60 anticancer function.
Firstly, 50 mg PPM60-A,PPM60-B,PPM60-C,PPM60-D were chemically modified by chlorosulfonic acid-pyridine method. 61.8 mg、79.0 mg、63.2 mg、71.9 mg SPPM60-A, SPPM60-B,SPPM60-C,SPPM60-D, modified compounds with 1.28、1.63、1.31、1.49 substituted degrees were obtained.
Secondly,the activities of PPM60 and SPPM60 on K562 cells were studied by observing their effects on cell proliferation and cell cycle. MTT colourimetry demonstrated that PPM60 inhibited the proliferation of K562 was stronger than SPPM60. After 48-hour treatment with 400μg/ml, PPM60 inhibited the growth of K562 remarkably by 32%, while SPPM60 just had 16%. Wright stain and Ho.33342/PI double fluorescence labeled staining were used to observe cell morphology. PPM60 induced K562 underwent some morphology changes as follows: cell size and nuclear diameter were reduced, chromatin condensated, cytoplasm was more abundant, reduction in the proportion of nuclear plasma, cell membrane integrity but did not appear smooth, and certain apotosia cells. There were no apparent morphology differences between SPPM60 group and control group. The analysis of cell cycle distribution was performed by flow cytometry. The result showed that PPM60 could stop K562 cells in G0/G1 phase. With an accumulation of cells in G0/G1 phase and an inducement to cell apotosis. SPPM60 had little effect on cell cycle.
Thirdly, the activities of PPM60 and SPPM60 on K562 cells were studied by observing their effects on cytosolic free calcium concentration([Ca2+]i) and reactive oxygen species(ROS). After cells were incubated with Fura-2/AM or DCFH-DA fluorescent probe, the concentration of cytosolic free calcium was measured by fluorescence spectrophotometer. After 24-hour, 48-hour, 72-hour treatment, PPM60 increased [Ca2+]i and ROS remarkably, while SPPM60 induced [Ca2+]i or had no apparent effect. The activities of PPM60 and SPPM60 on K562 cells were studied by observing their effects on cell superoxide dismutase(SOD). Within 72 hours, PPM60 induced SOD vitality while there were no conspicuous differences between SPPM60 group and control group. After 12-hour, 24-hour, 48-hour, 72-hour treatment, PPM60 had more effect than SPPM60 on increasing MDA .
The results suggested that:(1) PPM60 had more inhibitory effect on K562 cells,sulfation reduced PPM60 anticancer activity.(2)PPM60 could efficiently induce human leukemia cell apotosis and its mechanism may related to increase [Ca2+]i and ROS, prevent cell cycle, inhibit cell proliferation and growth.
一、PPM60的分离纯化及硫酸酯化修饰:采用氯磺酸-吡啶法分别对50mg PPM60-A、PPM60-B、PPM60-C、PPM60-D进行硫酸酯化改性,得到暗黄色产物SPPM60-A、SPPM60-B、SPPM60-C、SPPM60-D61.8mg、79.0mg、63.2mg、71.9mg。用氯化钡-明胶比浊法鉴定其硫酸根含量并计算取代度分别为1.28、1.63、1.31、1.49。
二、PPM60硫酸酯化前后对K562细胞增殖能力及细胞周期的影响:MTT法检测发现PPM60对K562细胞的增殖的抑制作用明显强于SPPM60,400μg/mLPPM60或SPPM60作用K562细胞48h时抑制率分别约达到32%和16%。瑞氏染色、Ho.33342/PI荧光双染观察PPM60或SPPM60对K562细胞形态的影响。经400μg/mLPPM60作用48h后,细胞体积缩小,核直径减小,核染色质浓缩,胞质丰富,核浆比例降低,细胞膜完整但不光滑,并出现一定程度的凋亡;SPPM60组与对照组相比没有明显差别。流式细胞技术检测PPM60或SPPM60处理前后K562细胞周期分布的变化。PPM60组较对照组G0/G1期细胞比例显著性增加,细胞周期发生了G0/G1期阻滞,并诱导凋亡发生。SPPM60处理组细胞细胞周期各个时相以及凋亡率与对照组相比,均没有显著性差异。
三、PPM60硫酸酯化前后对K562细胞[Ca2+]i和活性氧的影响:分别以Fura-2/AM和DCFH/DA为探针,荧光分光光度计检测PPM60或SPPM60处理前后[Ca2+]i和胞内ROS的变化。PPM60作用24h、48h、72h后,PPM60组[Ca2+]i与对照组相比均明显上升,SPPM60组[Ca2+]i与对照组各时间点均显著性降低;PPM60组胞内ROS水平明显升高,SPPM60组胞内ROS水平与对照组相比基本没有变化。黄嘌呤氧化酶法测定超氧化物歧化酶(SOD)活力法检测PPM60或SPPM60处理前后胞内SOD水平的变化。72h内K562细胞PPM60作用组的SOD活力较对照组有下降趋势;而SPPM60组胞内SOD活力与对照组相比,基本没有变化。TBA法检测PPM60或SPPM60处理前后胞内丙二醛(MDA)水平的变化。12h、24h、48h、72h后,PPM60组细胞内MDA与对照组相比都有所增加,SPPM60组胞内MDA水平高于对照组,但幅度甚小。
以上结果表明:(1)PPM60对K562细胞有较强的抑制作用,硫酸酯化修饰之后降低了其抑制作用。(2)PPM60抑制K562细胞的机制可能是升高细胞内钙离子和活性氧浓度,阻滞细胞周期于G0/G1期,并诱导K562细胞产生凋亡。
The anticancer research of polysaccharides from Pinus massoniana pollen(PPM60) and its sulfated derivative(SPPM60)has indicated that, SPPM60 inhibited the growth of human HepG2 cells in vitro,prevent cell cycle, inhibit cell proliferation and growth;PPM60 had no inhibitory effect on HepG2 cells growth. This research aims to determine the effects of PPM60 and SPPM60 on the proliferation and differentiation of human K562 cells, and then to give some theoretical and experimental roof for the research of SPPM60 anticancer function.
Firstly, 50 mg PPM60-A,PPM60-B,PPM60-C,PPM60-D were chemically modified by chlorosulfonic acid-pyridine method. 61.8 mg、79.0 mg、63.2 mg、71.9 mg SPPM60-A, SPPM60-B,SPPM60-C,SPPM60-D, modified compounds with 1.28、1.63、1.31、1.49 substituted degrees were obtained.
Secondly,the activities of PPM60 and SPPM60 on K562 cells were studied by observing their effects on cell proliferation and cell cycle. MTT colourimetry demonstrated that PPM60 inhibited the proliferation of K562 was stronger than SPPM60. After 48-hour treatment with 400μg/ml, PPM60 inhibited the growth of K562 remarkably by 32%, while SPPM60 just had 16%. Wright stain and Ho.33342/PI double fluorescence labeled staining were used to observe cell morphology. PPM60 induced K562 underwent some morphology changes as follows: cell size and nuclear diameter were reduced, chromatin condensated, cytoplasm was more abundant, reduction in the proportion of nuclear plasma, cell membrane integrity but did not appear smooth, and certain apotosia cells. There were no apparent morphology differences between SPPM60 group and control group. The analysis of cell cycle distribution was performed by flow cytometry. The result showed that PPM60 could stop K562 cells in G0/G1 phase. With an accumulation of cells in G0/G1 phase and an inducement to cell apotosis. SPPM60 had little effect on cell cycle.
Thirdly, the activities of PPM60 and SPPM60 on K562 cells were studied by observing their effects on cytosolic free calcium concentration([Ca2+]i) and reactive oxygen species(ROS). After cells were incubated with Fura-2/AM or DCFH-DA fluorescent probe, the concentration of cytosolic free calcium was measured by fluorescence spectrophotometer. After 24-hour, 48-hour, 72-hour treatment, PPM60 increased [Ca2+]i and ROS remarkably, while SPPM60 induced [Ca2+]i or had no apparent effect. The activities of PPM60 and SPPM60 on K562 cells were studied by observing their effects on cell superoxide dismutase(SOD). Within 72 hours, PPM60 induced SOD vitality while there were no conspicuous differences between SPPM60 group and control group. After 12-hour, 24-hour, 48-hour, 72-hour treatment, PPM60 had more effect than SPPM60 on increasing MDA .
The results suggested that:(1) PPM60 had more inhibitory effect on K562 cells,sulfation reduced PPM60 anticancer activity.(2)PPM60 could efficiently induce human leukemia cell apotosis and its mechanism may related to increase [Ca2+]i and ROS, prevent cell cycle, inhibit cell proliferation and growth.
引文
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