Abstract
In this study, we used nitrogen-doped titanium dioxide (N-TiO2) 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-TiO2 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/cm2), increasing N-TiO2 NP concentrations increased ROS levels to trigger autophagy-dependent megakaryocytic terminal differentiation in K562 cells. By contrast, an ROS challenge induced by high N-TiO2 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-TiO2. Pre-incubation of leukemic cells with ROS scavengers muted the effect of N-TiO2 NP-based PDT on cell fate, highlighting the upstream role of ROS in our system. In summary, PDT using N-TiO2 NPs provides an effective method of priming autophagy by ROS induction. The capability of photo-activated N-TiO2 NPs in obtaining desirable cellular outcomes represents a novel therapeutic strategy of cancer cells.
Highlights
Nanoparticles (NPs) are particles smaller than 100 nm in size and are of particular interest as cancer therapeutics because they preferentially localize to tumor sites and penetrate tissue and cellular barriers
The physicochemical properties of the synthetized N-TiO2 NPs have been reported in our previous study[17] and showed X-ray powder diffraction (XRD) peaks at 2θ= 25.3°, 37.8°, 48.1°, 53.1°, and 55.8° (Fig. 1A), which corresponded to the anatase form of TiO2
When compared to RPMI-1640, the N-TiO2 NPs in the medium stabilized with 10% fetal bovine serum (FBS) had, on average, a 10-fold lower hydrodynamic size distribution (92–98 nm), which is suitable for cellular penetration based on previous research[14,15,16]
Summary
Nanoparticles (NPs) are particles smaller than 100 nm in size and are of particular interest as cancer therapeutics because they preferentially localize to tumor sites and penetrate tissue and cellular barriers. We and others, reported that N-TiO2 NPs exhibit remarkable ROS-dependent cytotoxic and apoptotic activities upon visible-light irradiation in several cancerous cell lines, including HeLa and K562 cells[18,19,40]. We chose the human leukemia cell line K562 because this experimental model of chronic myelogenous leukemia (CML) enables simultaneous evaluation of multiple cellular outcomes This includes the differentiation toward different lineages (i.e., erythroid, macrophage and megakaryocyte lineages) and various death modes (i.e., apoptosis, autophagy, necrosis and necroptosis)[41]. Our results reveal that upon visible-light irradiation of N-TiO2 NPs, an ROS-mediated autophagic response occurred that could be fine-tuned to selectively induce differentiation or apoptosis in leukemia K562 cells
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