Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture.
Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture.
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作者：
S. Hill;D. Blask
由于褪黑激素，松果体的主要激素，已被证明可以抑制乳腺肿瘤的生长在人类乳腺癌的动物模型中，我们研究的假设，这吲哚胺有可能抑制乳腺癌的生长，直接抑制细胞增殖的雌激素反应的人乳腺癌细胞系MCF-7的培养作为例证。褪黑激素的浓度（10（-9）M; 10（-11）M），对应于夜间人体血液中的生理水平，显著抑制（P <0.001）细胞增殖，通过DNA含量或血细胞计数器细胞计数测量，抑制率高达60%至78%。褪黑激素的抑制作用是可逆的，因为在用不含褪黑激素的新鲜培养基替换含褪黑激素的培养基后，MCF-7细胞的对数生长恢复。不仅在药理学浓度（10（-7）M; 10（-5）M）或亚生理浓度（10（-15）M; 10（-13）M）下褪黑激素均不存在抑制作用，而且褪黑激素也不能抑制人包皮成纤维细胞或雌激素受体阳性人子宫内膜癌细胞系RL 95 -2的增殖。透射和扫描电子显微镜显示了几个形态学的变化，与褪黑激素的抑制细胞生长。暴露于褪黑激素仅4天后，MCF-7细胞表现出表面微绒毛数量减少，核肿胀，细胞质和核糖体脱落，线粒体嵴破坏，滑面内质网囊泡形成，自噬空泡数量增加。这些结果支持这一假设，褪黑激素，在生理浓度下，发挥直接的，但可逆的，抗增殖作用的MCF-7细胞生长的文化。这种抗增殖作用与这些细胞超微结构特征的显著变化有关，提示亚致死但可逆的细胞损伤。
Since melatonin, the major hormone of the pineal gland, has been shown to inhibit the growth of mammary tumors in animal models of human breast cancer, we examined the hypothesis that this indoleamine has the potential to inhibit breast cancer growth by directly inhibiting cell proliferation as exemplified by the growth of the estrogen-responsive human breast cancer cell line MCF-7 in culture. Concentrations of melatonin (10(-9) M; 10(-11) M), corresponding to the physiological levels present in human blood during the evening hours, significantly inhibited (P less than 0.001) cell proliferation by as much as 60% to 78% as measured by either DNA content or hemocytometer cell counts. Melatonin's inhibitory effect was reversible since the logarithmic growth of MCF-7 cells was restored after melatonin-containing medium was replaced with fresh medium lacking melatonin. Not only was the inhibitory effect of melatonin absent at either pharmacological (10(-7) M; 10(-5) M) or subphysiological (10(-15) M; 10(-13) M) concentrations, but melatonin also failed to inhibit the proliferation of either human foreskin fibroblasts or the estrogen receptor-positive human endometrial cancer cell line RL95-2. Both transmission and scanning electron microscopy revealed several morphological changes that correlated with melatonin's inhibition of cell growth. After just 4 days of exposure to melatonin, MCF-7 cells exhibited reduced numbers of surface microvilli, nuclear swelling, cytoplasmic and ribosomal shedding, disruption of mitochondrial cristae, vesiculation of the smooth endoplasmic reticulum, and an increase in the numbers of autophagic vacuoles. These results support the hypothesis that melatonin, at physiological concentrations, exerts a direct but reversible, antiproliferative effect on MCF-7 cell growth in culture. This antiproliferative effect is associated with striking changes in the ultrastructural features of these cells suggestive of a sublethal but reversible cellular injury.