The therapeutic potential of redox-active nanoscale materials as antioxidant- or reactive oxygen species (ROS)-inducing agents was intensely studied. Herein, we demonstrate that the synthesized and characterized GdVO4:Eu3+ and LaVO4:Eu3+ nanoparticles, which have been already shown to have redox-active, anti-inflammatory, antibacterial, and wound healing properties, both in vitro and in vivo, worsen oxidative stress of L929 cells triggered by hydrogen peroxide or tert-butyl hydroperoxide (tBuOOH) at the concentrations that are safe for intact L929 cells. This effect was observed upon internalization of the investigated nanosized materials and is associated with the cleavage of caspase-3 and caspase-9 without recruitment of caspase-8. Such changes in the caspase cascade indicate activation of the intrinsic caspase-9-dependent mitochondrial but not the extrinsic death, receptor-mediated, and caspase-8-dependent apoptotic pathway. The GdVO4:Eu3+ and LaVO4:Eu3+ nanoparticle-induced apoptosis of oxidatively compromised L929 cells is mediated by ROS overgeneration, Ca2+ overload, endoplasmic reticulum stress-associated JNK (c-Jun N-terminal kinase), and DNA damage-inducible transcript 3 (DDIT3). Our findings demonstrate that GdVO4:Eu3+ and LaVO4:Eu3+ nanoparticles aggravate the oxidative stress-induced damage to L929 cells, indicating that they might potentially be applied as anti-cancer agents.

BIOCEV 1st Faculty of Medicine Charles University Průmyslová 595 25250 Vestec Czech Republic

Department of Biochemistry 5 N Karazin Kharkiv National 4 Svobody Sq 61022 Kharkiv Ukraine

Department of Cryobiochemistry Institute for Problems of Cryobiology and Cryomedicine of the National Academy of Sciences of Ukraine 23 Pereyaslavskaya Str 61015 Kharkiv Ukraine

Department of Nanostructured Materials Institute for Scintillation Materials of the National Academy of Sciences of Ukraine 60 Nauky Ave 61072 Kharkiv Ukraine

Institute of Health National University of Water and Environmental Engineering 11 Soborna Str 33028 Rivne Ukraine

ISIS Neutron and Muon Source Rutherford Appleton Laboratory Harwell Oxford Didcot OX11 0QX UK

Research Institute of Experimental and Clinical Medicine Kharkiv National Medical University 4 Nauky Ave 61022 Kharkiv Ukraine

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