Doxorubicin-induced senescence through NF-κB affected by the age of mouse mesenchymal stem cells
Doxorubicin-induced senescence through NF-κB affected by the age of mouse mesenchymal stem cells
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DOI：
10.1002/jcp.29140
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发表时间：
2019-09-13
影响因子：
5.6
通讯作者：
Hassan, Jalal
中科院分区：
文献类型：
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作者：
Dezfouli, Ali Bashiri;Salar-Amoli, Jamileh;Hassan, Jalal
衰老被认为是许多抗癌药物的一种防御机制。这一并发症的特点是细胞外观和内部结构的不同，这是功能障碍的基础。在本实验中，从不同年龄的Balb/c小鼠(1月龄、8月龄和16月龄)的骨髓中分离的间充质干细胞(MSCs)对阿霉素诱导的衰老进行了研究。此外，还研究了阿霉素在培养液中的动力学，以比较不同年龄的MSCs对药物的吸收率。采用夹心ELISA法检测核因子-kappaB活性，碘化丙啶染色检测细胞周期，流式荧光原位杂交(Flow-FISH)检测端粒长度，特异性染色检测β-半乳糖苷酶活性。采用高效液相色谱技术测定了一种介质中的阿霉素。阿霉素作用后，细胞端粒显著缩短，细胞周期停滞于G2期，β-半乳糖苷酶活性增强。有趣的是，在所有年龄组中都观察到了核因子-kappaB水平的升高。1个月和8个月龄的MSCs对端粒缩短的敏感度分别最高和最低。与Flow-FISH结果一致的是，治疗后年轻MSCs的β-半乳糖苷酶活性更高。统计分析表明，端粒长度缩短与G2期停止相关。对于所获得的动力学方程，所有年龄的MSCs对阿霉素的吸收速率遵循相同的趋势。综上所述，在年轻的MSCs中，与其他两个年龄组相比，年轻MSCs中参与阿霉素诱导衰老的某些元素的变化受细胞年龄的影响更显著。因此，这些变化的模式可以为开发抗癌治疗策略提供新的见解。
The senescence is proposed as a defense mechanism against many anticancer drugs. This complication is marked by differences in cell appearance and inner structures underlying the impairment in function. In this experiment, doxorubicin-induced senescence was assessed in mesenchymal stem cells (MSCs) isolated from the bone marrow of different-aged Balb/c mice (1, 8, and 16 months old). In addition, doxorubicin kinetics in culture medium were investigated to compare the drug absorption rate by different-aged MSCs. Several methods were exerted including Sandwich ELISA for NF-kappa B activation, propidium iodide staining for cell cycle analysis, Flow-fluorescent in-situ hybridization (Flow-FISH) assay for telomere length measurement, and specific staining for evaluation of beta-galactosidase. Determination of doxorubicin in a medium was performed by high-performance liquid chromatography technique. Following doxorubicin exposure, cells underwent substantial telomere shortening, cell cycle arresting in G2 phase, and increased beta-galactosidase activity. Interestingly, the enhanced level of NF-kappa B was observed in all age groups. The highest and lowest sensitivity to telomere shortening attributed to 1- and 8-month-old MSCs, respectively. In consistent with Flow-FISH results, the beta-galactosidase activity was higher in young-aged MSCs after treatment. Statistical analysis indicated a correlation between the reduction of telomere length and cessation in G2 phase. Regarding the obtained kinetics equations, the rate of doxorubicin absorption by all aged MSCs followed the same trend. In conclusion, the changing of some elements involved in doxorubicin-induced senescence can be affected by the age of the cells significantly in young MSCs than two other age groups. Hereupon, these changing patterns can open new insights to develop anticancer therapeutic strategies.