Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles

Abstract

Oxidative stress, mainly contributed by reactive oxygen species (ROS), has been implicated in pathogenesis of several diseases. We review two primary examples; fibrosis and cancer. In fibrosis, ROS promote activation and proliferation of fibroblasts and myofibroblasts, activating TGF-β pathway in an autocrine manner. In cancer, ROS account for its genomic instability, resistance to apoptosis, proliferation, and angiogenesis. Importantly, ROS trigger cancer cell invasion through invadopodia formation as well as extravasation into a distant metastasis site. Use of antioxidant supplements, enzymes, and inhibitors for ROS-generating NADPH oxidases (NOX) is a logical therapeutic intervention for fibrosis and cancer. We review such attempts, progress, and challenges. Lastly, we review how nanoparticles with inherent antioxidant activity can also be a promising therapeutic option, considering their additional feature as a delivery platform for drugs, genes, and imaging agents.

Keywords: Antioxidant; Cancer; Fibrosis; Metastasis; Nanoparticles; ROS.

Graphical abstract

Fig. 1

Sources of ROS and key ROS molecules in signaling. ROS generation is a cascade of reaction initiated by the production of O₂^•− inside the cells, contributed by endogenous and exogenous cellular sources. Molecular oxygen is reduced to superoxide anion (O₂^•−) by enzymes such as NOX and nitric oxide synthases (NOS), or as by-products of redox reactions in mitochondrial respirations. O₂^•−, being cell-impermeant molecule, is then rapidly dismutated to H₂O₂ either spontaneously or enzymatically by antioxidant enzyme superoxide dismutases (SODs). The intracellular removal of H₂O₂ can be categorized into three different mechanisms: 1) by the action of catalase (CAT) and glutathione peroxidases (GPx) which reduces H₂O₂ to water, 2) through conversion of H₂O₂ into hypochlorous acid (HOCl) and ¹O₂ by the heme enzyme myeloperoxidase (MPO) the neutrophils, which results in antimicrobial activity, and 3) by Fenton reaction whereby H₂O₂ is converted to the highly reactive OH^• through oxidation of Fe²⁺ to Fe³⁺. The OH^• produced will then react with H₂O₂ to form O₂^•−, which, again, reacts with H₂O₂ to form OH^• and OH⁻, as a part of Haber-Weiss reaction.

Fig. 2

ROS contribute to the induction and persistence of TGF-β-mediated fibrosis. The presence of ROS induces the conversion of latent TGF-β complex to its active form, which binds to its receptor and triggers signaling pathways such as SMAD2/3, PI3K, and JNK. This in turn increases the transcriptional activity of various pro-fibrotic genes, such as NOX4, αSMA, and COL I. Increase in NOX4 expression also results in ROS generation, which leads activation of other ROS-dependent signaling transduction pathways such as, NFκB and JNK. Elevated ROS also causes irreversible DNA damage, through oxidization of its bases. Together, enhanced ROS and activated TGF-β signaling contributes to proliferation and transdifferentiation of fibroblast cells into myofibroblasts, and excessive ECM deposition leading to fibrosis.

Fig. 3

ROS play multiple roles in cancer progression. ROS generated by multiple sources including chemotherapeutics, radiation, inflammation, and hypoxia conditions contributes to genomic instability of the cancer cells, survival, resistance to apoptosis, proliferation, angiogenesis, invasion (through invadopodia formation), as well as extravasation into a distant metastasis site.

Fig. 4

Structure of NADPH oxidase family. (A) NOX1 activity requires p22phox, NOXO1 and NOXA1, and the small GTPase Rac. (B) NOX2 requires p22phox, p47phox, p67phox, and Rac. (C) NOX3 requires p22phox and NOXO1. (D) NOX4 requires p22phox, it is constitutively active without the requirement for other cytosolic subunits. (E) and (F): NOX5, DUOX1, and DUOX2 are activated by Ca²⁺ and do not appear to require subunits. Reproduced with permission from The American Physiological Society

Fig. 5

Intradermal injection of HSP47 siRNA (siHSP47) delivered with an antioxidant mesoporous silica-based nanoparticle in the bleomycin-induced skin fibrosis mouse model. (A) Dosing scheme of bleomycin induction and the siRNA-nanoparticle treatment. (B) Representative images of skin sections stained with hematoxylin and eosin (H&E), scale bar=200 µm. (C) Dermal thickness measured from skin sections in (B). Expression levels of (D) HSP47 and (E) NOX4 proteins as well as (F) α-SMA- and (G) COL I-positive area of skin sections harvested upon sacrifice. Immunofluorescence images can be found in ref . Reproduced with modification (permission from Elsevier [169]).