Fig. 3
From: Nanoparticles of Titanium and Zinc Oxides as Novel Agents in Tumor Treatment: a Review
Molecular mechanisms of reactive oxygen species (ROS)-mediated cell death pathways. Activated by ultraviolet (UV) radiation or ultrasound (US) wave, nanoparticles of titanium dioxide (TiO2 NPs) and zinc oxide (ZnO NPs) induce ROS-mediated cell apoptosis, autophagy or necrosis. The increase of ROS level in cytoplasm results in thioredoxin (Trx) oxidation and apoptosis signal-regulating kinase 1 (ASK1) activation. ASK1 phosphorylates mitogen-activated protein kinases (ERKs, JNKs, p38 MAPKs) that control the AP-1-mediated synthesis of pro- (Bak, Bax) and anti-apoptotic (Bcl-2, Bcl-xL) proteins, as well as death ligands (FasL), thus promoting the cell apoptosis. Likewise, ERKs promote the cell apoptosis trough attenuation of activity of AKT kinase that controls the NF-κB-mediated synthesis of Bcl-2 and Bcl-xL proteins. The oxidative damages of mitochondrion result in dissipation of mitochondrial membrane potential (ΔΨm), decrease of ATP level and release of cytochrome c (Cyt. c) to the cytosol. Cyt. c, binding with apoptotic protease activating factor 1 (Apaf-1), induces the caspase-dependent apoptosis. The increase of ROS level in nucleus results in the activation of ataxia telangiectasia mutated (ATM), as well as ataxia telangiectasia and Rad 3-related (ATR) kinases that induce the p53-mediated apoptosis and account for the increase of DNA double-strand breaks marker (γH2AX) level. The ROS-induced endoplasmic reticulum stress results in the JNK1-mediated increase of pro-autophagic protein (Beclin-1) level and the AMPK-mediated inhibition of autophagic inhibitor, mammalian target of rapamycin (mTOR) kinase. Both processes lead to the cell autophagy. The oxidative injuries of plasma membrane result in the downregulation of plasma membrane calcium ATPase 1 (PMCA1), in the decrease of ATP level and the increase of Ca2+ level. As a consequence, the cell necrosis follows