Abstract
Cerium oxide nanoparticles (CNPs) are potent radical scavengers protecting cells from oxidative insults, including ionizing radiation. Here we show that CNPs prevent X-ray-induced oxidative imbalance reducing DNA breaks on HaCat keratinocytes, nearly abating mutagenesis. At the same time, and in spite of the reduced damage, CNPs strengthen radiation-induced cell cycle arrest and apoptosis outcome, dropping colony formation; notably, CNPs do not possess any intrinsic toxicity toward non-irradiated HaCat, indicating that they act on damaged cells. Thus CNPs, while exerting their antioxidant action, also reinforce the stringency of damage-induced cell integrity checkpoints, promoting elimination of the “tolerant” cells, being in fact radio-sensitizers. These two contrasting pathways are mediated by different activities of CNPs: indeed Sm-doped CNPs, which lack the Ce3+/Ce4+ redox switch and the correlated antioxidant action, fail to decrease radiation-induced superoxide formation, as expected, but surprisingly maintain the radio-sensitizing ability and the dramatic decrease of mutagenesis. The latter is thus attributable to elimination of damaged cells rather than decreased oxidative damage. This highlights a novel redox-independent activity of CNPs, allowing selectively eliminating heavily damaged cells through non-toxic mechanisms, rather reactivating endogenous anticancer pathways in transformed cells.
Highlights
Cerium oxide nanoparticles (CNPs) are attracting much interest in biomedical applications for their anti-oxidant properties provided by the Ce3+/Ce4+ redox couple on the nanoparticles surface, which combine catalase- and superoxide dismutase (SOD)-mimetic activities scavenging hydrogen peroxide and superoxides in a self-regenerating manner (Das et al, 2013)
CNPs show additional intriguing anticancer properties: they ameliorate the effect of radiotherapy increasing killing of tumor cells (Wason et al, 2013), a major issue considering that cancer cell radio-resistance is a main obstacle to successful radiotherapy; CNPs seem to be preferentially toxic in cancer vs. non-transformed cells (Sack et al, 2014)
It has been proposed that CNPs dissolution occurring in particular conditions such as, e.g., acidic environment at pH ≤ 4 (Schwabe et al, 2014) or irradiation in water media (Asghar et al, 2017), may exert noxious effect, through liberation of the cytotoxic Ce4+ ions (Huang et al, 2010); an additional effect of the acidic environment is the inhibition of the catalase-mimetic activity of CNPs while the SOD-mimetic ability is preserved: this would lead to accumulation of H2O2, more toxic than superoxides, and a paradoxical oxidative stress (Perez et al, 2008)
Summary
Cerium oxide nanoparticles (CNPs) are attracting much interest in biomedical applications for their anti-oxidant properties provided by the Ce3+/Ce4+ redox couple on the nanoparticles surface, which combine catalase- and superoxide dismutase (SOD)-mimetic activities scavenging hydrogen peroxide and superoxides in a self-regenerating manner (Das et al, 2013). It has been proposed that CNPs dissolution occurring in particular conditions such as, e.g., acidic environment at pH ≤ 4 (Schwabe et al, 2014) or irradiation in water media (Asghar et al, 2017), may exert noxious effect, through liberation of the cytotoxic Ce4+ ions (Huang et al, 2010); an additional effect of the acidic environment is the inhibition of the catalase-mimetic activity of CNPs while the SOD-mimetic ability is preserved: this would lead to accumulation of H2O2, more toxic than superoxides, and a paradoxical oxidative stress (Perez et al, 2008) Such interpretations, must face the fact that on one side, pH > 4 does not cause CNPs alterations, and on the other, tissues and cells, though stressed or transformed, would collapse at pH ≤ 4: alternative explanations are required to understand the mechanism of the non-redox activities of CNPs
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