Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran.
Cell and Molecular Biology Department, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran.
Sci Rep. 2016 Oct 4;6:34413. doi: 10.1038/srep34413.
In this study, we used nitrogen-doped titanium dioxide (N-TiO) NPs in conjugation with visible light, and show that both reactive oxygen species (ROS) and autophagy are induced by this novel NP-based photodynamic therapy (PDT) system. While well-dispersed N-TiO NPs (≤100 μg/ml) were inert, their photo-activation with visible light led to ROS-mediated autophagy in leukemia K562 cells and normal peripheral lymphocytes, and this increased in parallel with increasing NP concentrations and light doses. At a constant light energy (12 J/cm), increasing N-TiO NP concentrations increased ROS levels to trigger autophagy-dependent megakaryocytic terminal differentiation in K562 cells. By contrast, an ROS challenge induced by high N-TiO NP concentrations led to autophagy-associated apoptotic cell death. Using chemical autophagy inhibitors (3-methyladenine and Bafilomycin A1), we confirmed that autophagy is required for both terminal differentiation and apoptosis induced by photo-activated N-TiO. Pre-incubation of leukemic cells with ROS scavengers muted the effect of N-TiO NP-based PDT on cell fate, highlighting the upstream role of ROS in our system. In summary, PDT using N-TiO NPs provides an effective method of priming autophagy by ROS induction. The capability of photo-activated N-TiO NPs in obtaining desirable cellular outcomes represents a novel therapeutic strategy of cancer cells.
在这项研究中，我们使用氮掺杂二氧化钛（N-TiO）纳米粒子与可见光结合，并表明这种新型基于纳米粒子的光动力疗法（PDT）系统会同时诱导活性氧（ROS）和自噬。虽然分散良好的 N-TiO 纳米粒子（≤100μg/ml）是惰性的，但它们在可见光下的光激活会导致白血病 K562 细胞和正常外周淋巴细胞中的 ROS 介导的自噬，并且这种自噬与 NP 浓度和光剂量的增加呈平行关系。在恒定的光能量（12 J/cm）下，增加 N-TiO NP 浓度会增加 ROS 水平，从而触发 K562 细胞中依赖自噬的巨核细胞终末分化。相比之下，高浓度 N-TiO NP 引起的 ROS 挑战会导致自噬相关的细胞凋亡。使用化学自噬抑制剂（3-甲基腺嘌呤和巴弗洛霉素 A1），我们证实自噬是光激活 N-TiO 诱导的终末分化和凋亡所必需的。预先孵育白血病细胞中的 ROS 清除剂会减弱 N-TiO NP 基于 PDT 对细胞命运的影响，这突出了 ROS 在我们系统中的上游作用。总之，使用 N-TiO NPs 的 PDT 通过 ROS 诱导提供了一种有效的自噬引发方法。光激活的 N-TiO NPs 获得所需细胞结果的能力代表了一种新型的癌细胞治疗策略。
