Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, Hradec Králové, Czech Republic.
Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, Hradec Králové, Czech Republic.
Biomed Pharmacother. 2017 Nov;95:828-836. doi: 10.1016/j.biopha.2017.09.008. Epub 2017 Sep 10.
One approach to improve effect of chemotherapy is combination of classical cytostatic drugs with natural compounds, e. g. sesquiterpenes. In our previous study, sesquiterpenes β-caryophyllene oxide (CAO) and trans-nerolidol (NER) improved the anti-proliferative effect of doxorubicin (DOX) in intestinal cancer cell lines.
The present study was designed to evaluate the effect of CAO and NER on DOX efficacy, focusing on cell proliferation, migration, apoptosis and DOX accumulation in breast cancer cells MDA-MB-231 and MCF7 in vitro and in mice bearing solid Ehrlich tumors (EST) in vivo.
The impact of cytotoxic effect was assessed by the neutral red uptake test. The ability to migrate was tested using real-time measurement in x-CELLigence system. Expressions of molecules were examined using western blot analysis. The accumulation of DOX inside the cells using time lapse microscopy was observed. The mice with inoculated EST cells were treated repeatedly with DOX and DOX+CAO or DOX+NER and the growth of tumors were monitored. DOX concentrations in plasma and tumor were assayed using HPLC.
In MDA-MB-231, combination of DOX with CAO enhanced anti-proliferative effect and acted strongly synergistic. NER increased accumulation of DOX inside the cells; moreover combination DOX with NER suppressed migration ability in vitro. In vivo, apoptosis was activated especially in group treated with DOX and CAO. However, none of tested sesquiterpenes was able to improve DOX accumulation in tumors and DOX-mediated inhibition of tumor growth.
In conclusion, sesquiterpenes CAO and NER increased the efficacy of DOX in breast cancer cells in vitro, but did not improve its effect in vivo, in Ehrlich solid tumor bearing mice.
提高化疗效果的一种方法是将经典细胞抑制剂与天然化合物（例如倍半萜烯）结合使用。在我们之前的研究中，倍半萜烯β-石竹烯氧化物（CAO）和反式-橙花叔醇（NER）改善了阿霉素（DOX）在肠癌细胞系中的抗增殖作用。
本研究旨在评估 CAO 和 NER 对 DOX 疗效的影响，重点关注 DOX 在体外乳腺癌细胞 MDA-MB-231 和 MCF7 中的增殖、迁移、凋亡和积累，以及在荷实体 Ehrlich 肿瘤（EST）小鼠体内的效果。
通过中性红摄取试验评估细胞毒性作用的影响。使用 x-CELLigence 系统实时测量评估迁移能力。使用 Western blot 分析检测分子表达。使用延时显微镜观察 DOX 在细胞内的积累。用 DOX 和 DOX+CAO 或 DOX+NER 重复处理接种 EST 细胞的小鼠，并监测肿瘤的生长。使用 HPLC 测定血浆和肿瘤中的 DOX 浓度。
在 MDA-MB-231 中，DOX 与 CAO 联合使用增强了抗增殖作用，并具有强烈的协同作用。NER 增加了 DOX 在内细胞中的积累；此外，DOX 与 NER 联合使用抑制了细胞的迁移能力。在体内，特别是在用 DOX 和 CAO 处理的组中，激活了细胞凋亡。然而，测试的任何一种倍半萜烯都不能改善 DOX 在肿瘤中的积累，也不能改善 DOX 抑制肿瘤生长的作用。
总之，倍半萜烯 CAO 和 NER 提高了 DOX 在体外乳腺癌细胞中的疗效，但在荷实体 Ehrlich 肿瘤小鼠中并未改善其体内效果。
