A POSSIBLE MECHANISM FOR THE CYTOTOXICITY OF A POLYACETYLENIC ALCOHOL, PANAXYTRIOL - INHIBITION OF MITOCHONDRIAL RESPIRATION
A POSSIBLE MECHANISM FOR THE CYTOTOXICITY OF A POLYACETYLENIC ALCOHOL, PANAXYTRIOL - INHIBITION OF MITOCHONDRIAL RESPIRATION
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DOI：
10.1007/bf00689447
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发表时间：
1995-02-01
影响因子：
3
通讯作者：
KATANO, M
中科院分区：
文献类型：
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作者：
MATSUNAGA, H;SAITA, T;KATANO, M
人参三醇一种聚炔醇，人参三醇，从人参C. A. Meyer抑制体外肿瘤细胞生长和移植到小鼠体内的B16黑色素瘤生长。我们的初步研究表明人参三醇定位于人乳腺癌细胞（Breast M25-SF）的线粒体。本研究旨在探讨人参三醇对乳腺癌M25-SF细胞线粒体结构和功能的影响。结果表明，人参三醇快速抑制乳腺M25-SF中的细胞呼吸并破坏细胞能量平衡。在11.3和180 μ M之间的浓度下，人参三醇在2小时内引起线粒体脱氢酶对四唑转化的剂量依赖性抑制（MTT测定）。用180 μ M人参三醇处理1小时，导致具有用罗丹明-123预染色的线粒体的细胞中罗丹明-123的显著损失（通过流式细胞术）。用180 μ M以上的人参三醇处理后1小时内，用电子显微镜在乳腺M25-SF的线粒体中观察到特定的毒性变化。这些数据表明，180 μ M人参三醇迅速破坏乳腺M25-SF细胞能量平衡和呼吸，并表明人参三醇可能降低细胞ATP浓度。用180 μ M人参三醇处理后，细胞ATP水平在1小时后为对照细胞的40%。ATP耗竭先于细胞活力丧失。在没有线粒体的人红细胞中既没有发现ATP耗竭也没有发现细胞溶解。因此，由线粒体呼吸的直接抑制引起的ATP耗竭是人参三醇细胞毒性的关键早期事件。
A polyacetylenic alcohol, panaxytriol, isolated from Panax ginseng C. A. Meyer inhibits both tumor cell growth in vitro and the growth of B16 melanoma transplanted into mice. Our preliminary studies indicated that panaxytriol localizes to the mitochondria in human breast carcinoma cells (Breast M25-SF). This study focused on the effects of panaxytriol on mitochondrial structures and function in Breast M25-SF. The results indicate that panaxytriol rapidly inhibits cellular respiration and disrupts cellular energy balance in Breast M25-SF. At concentrations between 11.3 and 180 mu M, panaxytriol causes a dose-dependent inhibition of the conversion of the tetrazolium (MTT assay) by mitochondrial dehydrogenase within 2 h. A l-h treatment with 180 mu M panaxytriol causes a significant loss of rhodamine-123 from cells with mitochondria prestained with rhodamine-123 (by flow cytometry). Specific toxic changes were observed by electron microscopy in the mitochondria of Breast M25-SF within 1 h after treatment with more than 180 mu M panaxytriol. These data indicate that 180 mu M panaxytriol rapidly disrupts cellular energy balance and respiration in Breast M25-SF and suggest that panaxytriol may lower cellular ATP concentrations. After treatment with 180 mu M panaxytriol, cellular ATP levels were 40% of those in control cells after 1 h. ATP depletion preceded the loss of cellular viability. Neither ATP depletion nor cytolysis was found in human erythrocytes that have no mitochondria. Thus, ATP depletion resulting from a direct inhibition of mitochondrial respiration is a critical early event in the cytotoxicity of panaxytriol.