Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, Hubei 437100, P. R. China.
Department of Reparatory and Critical Care Medicine, the First Affiliated Hospital of Jilin University, Changchun 130021, P. R. China.
Int J Biol Sci. 2019 Jul 3;15(8):1755-1770. doi: 10.7150/ijbs.34878. eCollection 2019.
Diselenide-containing paclitaxel nanoparticles (SePTX NPs) indicated selectivity of cytotoxicity between cancerous and normal cells in our previous work. Herein, the mechanism is revealed by molecular biology in detail. Cancer cells and normal cells were treated with the SePTX NPs and cell proliferation was measured using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay and cell morphology. Measurement of reactive oxygen species (ROS) levels and biochemical parameters were employed to monitor oxidative stress of the cells. JC-1 assay was used to detect the mitochondrial dysfunction of the cells. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) analysis was used to detect apoptosis of the cells. Immunofluorescence analysis and western blotting were employed to monitor changes in signaling pathway-related proteins. Compared with PTX, SePTX NPs has a good selectivity to cancer cells and can obviously induce the proliferation damage of cancer cells, but has no significant toxicity to normal cells, indicating that SePTX NPs has a specific killing effect on cancer cells. The results of mechanism research show that SePTX NPs can successfully inhibit the depolymerization of microtubules and induce cell cycle arrest, which is related to the upregulation of p53 and CyclinB1. Simultaneously, SePTX NPs can successfully induce oxidative stress, cause mitochondrial dysfunction, resulting in mitochondrial pathway-mediated apoptosis, which is related to the upregulation of autophagy-related protein LC3-II. On the other hand, lewis lung cancer C57BL/6 mice were used to evaluate the anti-tumor effects of SePTX NPs . Our data show that SePTX NPs exhibited high inhibiting efficiency against the growth of tumors and were able to reduce the side effects. Collectively, these data indicate that the high antitumor effect and selective cytotoxicities of SePTX NPs is promising in future cancer therapy.
含二硒键的紫杉醇纳米粒（SePTX NPs）在我们之前的工作中显示出对癌细胞和正常细胞的细胞毒性选择性。在此，通过分子生物学详细揭示了其机制。用 SePTX NPs 处理癌细胞和正常细胞，并用 3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2-H-四唑溴盐（MTT）测定法和细胞形态来测量细胞增殖。测量活性氧（ROS）水平和生化参数来监测细胞的氧化应激。使用 JC-1 测定法来检测细胞的线粒体功能障碍。末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记（TUNEL）分析用于检测细胞凋亡。免疫荧光分析和蛋白质印迹用于监测信号通路相关蛋白的变化。与 PTX 相比，SePTX NPs 对癌细胞具有良好的选择性，可明显诱导癌细胞增殖损伤，但对正常细胞无明显毒性，表明 SePTX NPs 对癌细胞具有特异性杀伤作用。机制研究结果表明，SePTX NPs 可成功抑制微管解聚并诱导细胞周期停滞，这与 p53 和 CyclinB1 的上调有关。同时，SePTX NPs 可成功诱导氧化应激，引起线粒体功能障碍，导致线粒体途径介导的细胞凋亡，这与自噬相关蛋白 LC3-II 的上调有关。另一方面，使用 Lewis 肺癌 C57BL/6 小鼠评估了 SePTX NPs 的抗肿瘤作用。我们的数据表明，SePTX NPs 对肿瘤的生长表现出高抑制效率，并能够降低副作用。综上所述，这些数据表明 SePTX NPs 具有高抗肿瘤作用和选择性细胞毒性，在未来的癌症治疗中具有广阔的应用前景。
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