光激发C60富勒烯参与增强顺铂对耐药L1210细胞毒性的模式

D. Franskevych, S. Prylutska, I. Grynyuk, G. Pasichnyk, L. Drobot, O. Matyshevska, U. Ritter
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引用次数: 2

摘要

C60富勒烯作为一种生物医学应用的候选物受到了广泛的关注。由于其独特的结构和性质,C60富勒烯纳米颗粒有望在药物传递、癌症光动力治疗(PDT)和逆转肿瘤细胞多药耐药等方面发挥重要作用。本研究的目的是阐明光激发C60富勒烯依赖性增强顺铂对顺铂耐药白血病细胞毒性的可能分子机制。方法:采用稳定均相的原始C60富勒烯水胶体溶液(10-4 М,纯度99.5%)。用发光二极管灯(420 ~ 700 nm, 100 mW·cm-2)在微孔板上照射L1210R细胞积累的C60富勒烯。细胞进一步用Cis-Pt孵育至终浓度为1 μg/mL。Western blot分析显示p38 MAPK的激活。用流式细胞术估计细胞周期分布。使用荧光电位敏感探针TMRE (Tetramethylrhodamine Ethyl Ester)估计线粒体膜电位(Δψm)。结果:1 μg/mL浓度的Cis-Pt单独作用对L1210R细胞线粒体膜电位及细胞周期分布无明显影响。10-5M C60富勒烯处理的L1210R细胞辐照后,检测到ros敏感的促凋亡p38激酶的活化和subG1期细胞含量的增加。光激发C60富勒烯和Cis-Pt联合处理后,早期Δψm耗散,细胞向S期过渡受阻,长时间孵育后细胞大量聚集在促凋亡的subG1期。结论:两种药物的协同细胞毒活性可以推测光激C60富勒烯促进顺铂在抗顺铂白血病细胞中的积累。获得的数据可能对开发克服白血病细胞耐药性的新方法有用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mode of photoexcited C60 fullerene involvement in potentiating cisplatin toxicity against drug-resistant L1210 cells
Introduction: C60 fullerene has received great attention as a candidate for biomedical applications. Due to unique structure and properties, C60 fullerene nanoparticles are supposed to be useful in drug delivery, photodynamic therapy (PDT) of cancer, and reversion of tumor cells’ multidrug resistance. The aim of this study was to elucidate the possible molecular mechanisms involved in photoexcited C60 fullerene-dependent enhancement of cisplatin toxicity against leukemic cells resistant to cisplatin. Methods: Stable homogeneous pristine C60 fullerene aqueous colloid solution (10-4 М, purity 99.5%) was used in the study. The photoactivation of C60 fullerene accumulated by L1210R cells was done by irradiation in microplates with light-emitting diode lamp (420-700 nm light, 100 mW·cm-2). Cells were further incubated with the addition of Cis-Pt to a final concentration of 1 μg/mL. Activation of p38 MAPK was visualized by Western blot analysis. Flow cytometry was used for the estimation of cells distribution on cell cycle. Mitochondrial membrane potential (Δψm) was estimated with the use of fluorescent potential-sensitive probe TMRE (Tetramethylrhodamine Ethyl Ester). Results: Cis-Pt applied alone at 1 μg/mL concentration failed to affect mitochondrial membrane potential in L1210R cells or cell cycle distribution as compared with untreated cells. Activation of ROS-sensitive proapoptotic p38 kinase and enhanced content of cells in subG1 phase were detected after irradiation of L1210R cells treated with 10-5M C60 fullerene. Combined treatment with photoexcited C60 fullerene and Cis-Pt was followed by the dissipation of Δψm at early-term period, blockage of cell transition into S phase, and considerable accumulation of cells in proapoptotic subG1 phase at prolonged incubation. Conclusion: The effect of the synergic cytotoxic activity of both agents allowed to suppose that photoexcited C60 fullerene promoted Cis-Pt accumulation in leukemic cells resistant to Cis-Pt. The data obtained could be useful for the development of new approaches to overcome drug-resistance of leukemic cells.
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