ROS in cancer therapy: the bright side of the moon

Abstract

Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. It is now well accepted that moderate levels of ROS are required for several cellular functions, including gene expression. The production of ROS is elevated in tumor cells as a consequence of increased metabolic rate, gene mutation and relative hypoxia, and excess ROS are quenched by increased antioxidant enzymatic and nonenzymatic pathways in the same cells. Moderate increases of ROS contribute to several pathologic conditions, among which are tumor promotion and progression, as they are involved in different signaling pathways and induce DNA mutation. However, ROS are also able to trigger programmed cell death (PCD). Our review will emphasize the molecular mechanisms useful for the development of therapeutic strategies that are based on modulating ROS levels to treat cancer. Specifically, we will report on the growing data that highlight the role of ROS generated by different metabolic pathways as Trojan horses to eliminate cancer cells.

Fig. 1. Redox signaling and oxidative stress in normal and cancer cells.

The major signaling cascades induced by growth factor-stimulated ROS are highlighted on the left. The same pathways influence the cell cycle and affect the activity of transcription factors and genes that play roles in the cellular response to the hypoxic microenvironment. ROS also induce lipid peroxidation with commensurate electron leakage in mitochondria and the release of Ca²⁺ from intracellular stores. The main consequences of oxidative stress in cancer cells are illustrated on the right. Moderately elevated ROS induce oncogenes and inhibit tumor suppressor genes that, in turn, increase ROS levels. Ca²⁺ release induces PKC, while the expression of genes involved in the formation of new blood vessels and in the establishment of a boosted antioxidant system is enhanced. ROS also activate HDACs and have a dual effect on DNMTs with important outcomes for the expression of oncogenes and tumor suppressor genes. Oxidized bases trigger mutations and engage DNA repair enzymes.

Fig. 2. The three types of programmed cell death induced by elevated ROS levels in cancer cells.

ROS, in response to death-inducing ligands (TNFα and Fas), enhance the assembly of DISCs and the activation of effector caspases and reduce Bcl-2 activity or, as a consequence of increased permeability of mitochondrial PTPs, stimulate the intracytoplasmic release of cytochrome c, which interacts with Apaf-1 and procaspases and forms the apoptosome (apoptosis). ROS can also inhibit the negative regulators of autophagy (TORC1) and increase the formation of LC3-dependent autophagosomes (autophagy). Finally, high levels of ROS, induced by several receptor-interacting protein kinases (RIPs), increase p53 expression, which increases ROS levels via a mechanism that depends on intracellular iron (ferroptosis).

Fig. 3. Role of nuclear ROS in transcription and DNA damage.

ROS generated during nuclear receptor-induced transcription of target genes by the activity of lysine demethylases on lysine 9 in histone H3 must be controlled to prevent their accumulation. To this end, SOD1 reaches the nuclear space, while phosphorylation of H3S10 inhibits the rapid remethylation of the same lysine. If inhibitors of the H3S10 kinases are introduced as a Trojan horse together with nuclear receptor ligands, remethylation of H3K9 is quick, nuclear ROS accumulate, and unrepaired DNA damage triggers PCD.

Fig. 4. The two possible ROS-related anticancer therapeutic strategies.

The first approach is based on lowering ROS levels to counteract their role in cellular transformation; it is aimed at reducing the number of transformed cells by depriving them of fuel (represented in the upper right side of the figure as a lower proportion of transformed cells with respect to that of normal cells). The second approach is based on the consideration that cancer cells, with an antioxidant system already triggered, are more sensitive than their normal counterparts to further increases in ROS and are unable to achieve redox balance. Therefore, by inducing ROS under these metabolic conditions, a high percentage of the cells undergo death (represented in the lower right side of the figure, where transformed cells are depicted as apoptotic).