Department of Chemistry and Molecular Biology , University of Gothenburg , SE-412 96 Gothenburg , Sweden.
ACS Chem Neurosci. 2019 Apr 17;10(4):2060-2069. doi: 10.1021/acschemneuro.8b00714. Epub 2019 Feb 26.
Electrochemical measurements of exocytosis combined with intracellular vesicle impact electrochemical cytometry have been used to evaluate the effect of an anticancer drug, tamoxifen, on catecholamine release at the single-cell level. Tamoxifen has been used for over 40 years to treat estrogen receptor-positive breast cancers during both early stages of the disease and in the adjuvant setting. Tamoxifen causes memory and cognitive dysfunction, but the reasons for the cognitive impairment and memory problems induced by this anticancer drug are not well-known. We show that tamoxifen, through a nongenomic mechanism, can modulate both exocytosis and vesicle catecholamine storage in a model cell line. The results indicate that exocytosis is inhibited at high concentrations of tamoxifen and is stimulated at low levels. Tamoxifen also elicits a significant concentration-dependent change in total catecholamine content of single vesicles, while sub-nanomolar concentrations of the drug have stimulatory activity on the catecholamine content of vesicles. In addition, it has profound effects on storage at higher concentrations. Tamoxifen also reduces the intracellular free Ca but only at micromolar concentration, by acting on voltage-gated Ca channels, which likely affects neurotransmitter secretion.
电化学测量与细胞内囊泡冲击电化学细胞术相结合，已被用于评估一种抗癌药物他莫昔芬对儿茶酚胺在单细胞水平释放的影响。他莫昔芬已被用于治疗雌激素受体阳性乳腺癌 40 多年，无论是在疾病早期还是在辅助治疗中。他莫昔芬会导致记忆和认知功能障碍，但这种抗癌药物引起的认知障碍和记忆问题的原因尚不清楚。我们表明，他莫昔芬通过非基因组机制，可以调节模型细胞系中的胞吐作用和囊泡儿茶酚胺储存。结果表明，高浓度的他莫昔芬抑制胞吐作用，而低浓度的他莫昔芬刺激胞吐作用。他莫昔芬还引起单囊泡中单胺类物质含量的显著浓度依赖性变化，而药物的亚纳摩尔浓度对囊泡中单胺类物质的含量具有刺激作用。此外，在较高浓度下，他莫昔芬对储存也有深远的影响。他莫昔芬还通过作用于电压门控钙通道来降低细胞内游离钙，但只有在微摩尔浓度下才会降低，这可能会影响神经递质的分泌。
