Wroclaw University of Science and Technology, Dept. of Biomedical Engineering, Faculty of Fundamental Problems of Technology, 27 Wybrzeze Wyspianskiego St., 50-370 Wroclaw, Poland.
Wroclaw Medical University, Dept. of Hematology, Blood Neoplasms and Bone WroclawMarrow Transplantation,4 Pasteur St., 50-367 Wroclaw, Poland.
Biomed Pharmacother. 2018 Jan;97:1195-1203. doi: 10.1016/j.biopha.2017.11.040. Epub 2017 Nov 11.
Mechanical properties of biological structures play an important role in regulating cellular activities and are critical for understanding metabolic processes in cancerous cells and the effects of drugs. For some cancers, such as acute myeloid leukaemia, chemotherapy is one of preferential methods. However, due to the lack of selectivity to cancer cells, cytostatic agents cause toxicity to normal tissues. Here, we study the effect of doxorubicin (DOX) on the mechanical properties of DNA molecules, leukemic blast cells and erythrocytes, using optical tweezers. In addition, we controlled the subcellular distribution of the drug by confocal microscopy. Our results indicated that doxorubicin affects mechanical properties of cellular structures. In all cases the drug reduced mechanical strength of examined objects. For the leukemic cells the drug subcellular distribution was predominantly nuclear with some particulate cytoplasmic fluorescence. In erythrocytes, doxorubicin showed fluorescence mainly in cytoplasm and plasma membrane. The lowering of blast cells stiffness may be due to the interaction of doxorubicin with nuclear structures, especially with nucleic acids, as our studies with DNA confirmed. In addition, it is known that DOX inhibits the polymerization of actin and thus cytoskeletal modification may also be important in reducing of cell mechanical strength. In the case of erythrocytes - the non-nucleated cells, a significant effect on the decrease of cell stiffness, besides the cytoskeleton, may have the interaction of the drug with the cell membrane. Experiments with model phospholipid membranes confirmed that observed increase in cell elasticity originates, among other things, from the drug incorporation in the lipid membrane itself. The lowering of mechanical strength of leukemic cells may have an significant impact on the effectiveness of chemotherapy. However, the fact that doxorubicin interacts not only with proliferating cancer cells, but also with the health ones may explains the high toxicity of the drug at the therapeutic concentrations. Our observations also suggest that chemotherapy with doxorubicin may decrease the risk of vascular complications in acute leukemia, due to increasing the cell elasticity.
生物结构的力学性质在调节细胞活动中起着重要作用，对于理解癌细胞中的代谢过程和药物的作用至关重要。对于某些癌症，如急性髓系白血病，化疗是首选方法之一。然而，由于缺乏对癌细胞的选择性，细胞抑制剂会对正常组织造成毒性。在这里，我们使用光学镊子研究了阿霉素（DOX）对 DNA 分子、白血病细胞和红细胞的机械性质的影响，同时通过共聚焦显微镜控制药物的亚细胞分布。我们的结果表明，阿霉素会影响细胞结构的力学性质。在所有情况下，药物都会降低被检测物体的机械强度。对于白血病细胞，药物的亚细胞分布主要是核内，伴有一些颗粒状细胞质荧光。在红细胞中，阿霉素主要显示细胞质和质膜荧光。白血病细胞硬度的降低可能是由于阿霉素与核结构的相互作用，尤其是与核酸的相互作用，正如我们对 DNA 的研究所证实的那样。此外，已知 DOX 抑制肌动蛋白的聚合，因此细胞骨架的修饰也可能在降低细胞机械强度方面很重要。在红细胞这种无核细胞的情况下，除了细胞骨架之外，药物与细胞膜的相互作用可能对降低细胞硬度有重要影响。用模型磷脂膜进行的实验证实，观察到的细胞弹性增加，除其他外，源于药物本身掺入脂质膜。白血病细胞机械强度的降低可能会对化疗的效果产生重大影响。然而，阿霉素不仅与增殖的癌细胞相互作用，而且与健康细胞相互作用的事实可能解释了药物在治疗浓度下的高毒性。我们的观察还表明，由于细胞弹性增加，用阿霉素进行化疗可能会降低急性白血病中血管并发症的风险。
