摘要
锌是人体必需的微量元素，锌缺乏能引起人体多种疾病的发生，而镉是一种重金属元素，具有致癌、致畸、致突变作用。但有研究表明，镉可以诱导癌细胞凋亡，对多种癌症具有治疗作用。在欧美国家，前列腺癌导致的死亡率仅次于肺癌，位居第二。正常前列腺组织比其他软组织中的锌含量高10倍多，前列腺癌发生后，前列腺癌组织中的含锌量明显降低。正常情况下，前列腺组织中的[Zn~(2+])／[Cd~(2+)]处于平衡状态，而病理状态下，这种平衡遭到破坏从而导致多种前列腺疾病的发生。流行病学调查、细胞体外和动物体内试验都证实EGCG可以预防和治疗前列腺癌，EGCG在前列腺癌细胞中的生物学活性受金属离子存在的影响，但Zn~(2+)、Cd~(2+)与EGCG相互作用及其在前列腺癌细胞PC-3中的生物学行为至今未见报道。
本文利用前列腺癌细胞PC-3培养体系研究了Zn~(2+)、Cd~(2+)和EGCG对前列腺癌细胞PC-3生长状态的影响。结果表明，EGCG、Zn~(2+)和Cd~(2+)可以导致PC-3细胞形态结构变化，EGCG可以减轻Zn~(2+)和Cd~(2+)对PC-3细胞的损伤；80μmol／L的Zn~(2+)可以诱导PC-3细胞凋亡，20μmol／L的Cd~(2+)主要导致PC-3细胞坏死，而80μmol／L的EGCG处理并未观察到凋亡的PC-3细胞，三者导致的细胞死亡率与其使用剂量有关；三者均可降低PC-3细胞膜的U／S值，降低PC-3细胞膜的流动性，从而影响PC-3细胞膜的结构和功能。已有报道称金属离子增强EGCG对癌细胞的作用可能是因为二者形成络合物提高了EGCG的生物学活性，但其机理仍不清楚。本文体外合成Zn~(2+)、Cd~(2+)与EGCG络合物并应用于前列腺癌细胞PC-3，旨在验证Zn~(2+)、Cd~(2+)与EGCG络合作用对前列腺癌细胞的影响机理。MTT法实验结果发现，Zn~(2+)、Cd~(2+)均可增强EGCG对PC-3细胞生长的抑制作用，而络合物却减弱了这种作用；化学发光实验表明，Zn~(2+)、Cd~(2+)能增强EGCG清除羟基自由基的能力，清除率随处理浓度的增加而增加，在40，80，160μmol／L处理浓度下，Zn~(2+)／EGCG混合物和Cd~(2+)／EGCG混合物与EGCG相比都达到了显著或极显著水平，而络合物除了Zn-EGCG络合物在160μmol／L外均未达到显著水平；HPLC法测定其透膜率结果表明Zn~(2+)、Cd~(2+)可以增强EGCG的透膜率，但是络合物却减弱了EGCG的透膜率。这些结果都证明了Zn~(2+)、Cd~(2+)与EGCG形成络合物并非Zn~(2+)、Cd~(2+)增强EGCG对前列腺癌细胞作用的主要原因。
为了探讨Zn~(2+)、Cd~(2+)及EGCG防治前列腺癌的机理，本文选择最佳的处理浓度和处理时间，研究了Zn~(2+)、Cd~(2+)和EGCG对前列腺癌细胞PC-3线粒体功能以及细胞内氧化还原状态的影响。线粒体功能实验结果表明，EGCG、Zn~(2+)和Cd~(2+)可以直接与PC-3细胞线粒体作用并影响线粒体功能；EGCG、Zn~(2+)和Cd~(2+)通过诱导线粒体膜转换孔的开放、细胞色素C的释放、线粒体膜电位和膜流动性的下降等线粒体途径诱导细胞凋亡。细胞氧化还原状态实验结果表明，EGCG、Zn~(2+)和Cd~(2+)均可诱导PC-3细胞内的氧化应激，产生活性氧自由基，降低细胞膜的流动性，损伤细胞内的生物大分子等。
Zinc ion is indispensable to human health, and plays an important role in the occurrence of many diseases caused by the absence or excess of their intake. Cadmium is a kind of toxic metal to the human body and an inducer to cancers or tumors. However, previous papers reported that high doses of Cd~(2+), corresponding to acute exposure, could give rise to necrosis or apoptosis to the cells. As investigated before, the mortality caused by prostate cancer has been stood the second place among all diseases to be taken place in the human body. Also, from past reports total Zn~(2+) levels in the prostate are 10 times higher than in other soft tissues, and the ability of Zn~(2+) to be accumulated in the prostate is disappeared during prostate carcinogenesis. Practically, the metabolisms of Zn~(2+) and Cd~(2+) are in a balance in normal prostate glands. Moreover, if their balance was disturbed prostate diseases would be occurred. Depending on the epidemiology, cell scanning experiments in vitro and animal tests in vivo, it was primarily confirmed that EGCG could act as the prevention from prostate cancer. Meantime, the bioactivity of EGCG was significantly affected by metal ions. But so far, it has not been elucidated clearly about the interactions between Zn or Cd~(2+) and EGCG, and their behavior showed in androgen-insensitive human prostate tumor cells (PC-3) yet.
In the present dissertation, effects of EGCG, Zn~(2+) and Cd~(2+) on the growth of PC-3 cells were investigated. The results showed that EGCG, Zn~(2+) and Cd~(2+) brought the changes of PC-3 cells morphologically, and the effects of Zn~(2+) and Cd~(2+) in the presence of EGCG were decreased. The proliferation of PC-3 cells was suppressed by EGCG, Zn~(2+) and Cd~(2+) in a dose-dependent manner. 80μmol/L Zn~(2+) could induce apoptosis to PC-3 cells, and 20μmol/L Cd~(2+) could give rise to their necrosis, but, addition of 80μmol/L EGCG could not cause their apoptosis. Also, EGCG, Zn~(2+) or Cd~(2+) could lead to a decrease in membrane fluidity of PC-3 cells as evidenced by a decrease in U/S. Some published papers suggested that the possible reasons for the biological behavior of EGCG against human cancer cells were due to the formation of complexes of EGCG with metal ions. In fact, whether complex of EGCG with Zn~(2+) was a main functional component against prostate cancer was not clear up to now. The objective of this investigation was to explore mechanism of interactions of EGCG with Zn~(2+) or Cd~(2+)in the enhancement of Zn~(2+) or Cd~(2+) to inhibition of EGCG against PC-3 cells. MTT assay demonstrated that Zn~(2+) or Cd~(2+) increased the effects of EGCG against PC-3 cells, but their complexes decreased these kinds of effects obviously. From chemiluminescence tests, the free radical scavenging rate of mixture of EGCG and Zn~(2+) or Cd~(2+) was significantly different from the treatment with EGCG alone at 40, 80, 160μmol/L, but the free radical scavenging rate of Zn-EGCG or Cd-EGCG complex was not significantly different from EGCG except for Zn-EGCG complex at 160μmol/L. HPLC was employed to detect and quantify EGCG content in PC-3 cells. The results of HPLC analysis showed that Zn~(2+) and Cd~(2+) enhanced permeatability of EGCG to cytoplasm membrane, but Zn-EGCG or Cd-EGCG complex did not. Thus, we postulated that complex of EGCG with Zn~(2+) or Cd~(2+) was not able to the main functional component in coexisting system of EGCG with Zn~(2+) or Cd~(2+), which inhibited the growth of PC-3 cells.
In order to explore the mechanism of EGCG, Zn~(2+) and Cd~(2+) against PC-3 cells, we chose the best exposure period (24h) and optimal concentration to investigate the effects of EGCG, Zn~(2+), Cd~(2+) and EGCG in the presence of Zn~(2+) or Cd~(2+) on the function of mitochondria involved ROS of PC-3 cells. The results indicated that EGCG, Zn~(2+) and Cd~(2+) could interact directly with mitochondria and induce PC-3 cells death through the mitochondria-mediated apoptotic pathway. ROS might be responsible for the EGCG- and Cd~(2+)-mediated induction of apoptosis. EGCG, Zn~(2+) and Cd~(2+) could trigger oxidative stress of PC-3 cells to produce ROS, decrease membrane fluidity and destroy biomolecules.
引文
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