Oxidative Stress and ROS-Mediated Signaling in Leukemia: Novel Promising Perspectives to Eradicate Chemoresistant Cells in Myeloid Leukemia

Abstract

Myeloid leukemic cells are intrinsically under oxidative stress due to impaired reactive oxygen species (ROS) homeostasis, a common signature of several hematological malignancies. The present review focuses on the molecular mechanisms of aberrant ROS production in myeloid leukemia cells as well as on the redox-dependent signaling pathways involved in the leukemogenic process. Finally, the relevance of new chemotherapy options that specifically exert their pharmacological activity by altering the cellular redox imbalance will be discussed as an effective strategy to eradicate chemoresistant cells.

Keywords: ROS; ROS-based therapy; acute myeloid leukemia (AML); antioxidant systems; chemoreistance; oxidative stress.

Figure 1

Major sites of reactive oxygen species (ROS) production in leukemia cells. ROS are derived from different cellular compartments and enzymatic systems. The most significant source of ROS in the cell is represented by mitochondria, in which ROS are largely generated by the electron transport chain (ETC). Other ROS-producing mechanisms involve transmembrane NADPH oxidases (NOX), xanthine oxidoreductase in peroxisomes and protein disulfide isomerase (PDI) in endoplasmic reticulum (ER).

Figure 2

Schematic diagram depicting the main antioxidant systems in leukemia cells. The superoxide dismutase (SOD) catalyzes the dismutation of superoxide into molecular oxygen and hydrogen peroxide, which is then further processed by catalase. Intracellular SOD isoforms have different locations: SOD1 is located in the cytosol, SOD2 in mitochondria. The glutathione (GSH) antioxidant system comprises GSH, glutathione reductase (GR) and glutathione peroxidase (GPx). To perform its antioxidant function, GSH needs to be oxidized into GSSG via GPx. To restore reduced GSH levels, GSSG is converted by GR in a reaction that requires NADPH. The thioredoxin (TRX) antioxidant system involves TRX, peroxiredoxin (PRX) and thioredoxin reductase (TRXR). Reduced TRX catalyzes the reduction of disulfides within PRX. In this process TRX is oxidized (TRXox) and subsequently reduced (TRXred) by thioredoxin reductase (TRXR) through a NADPH-dependent mechanism.

Figure 3

ROS-dependent transduction signaling. ROS are important modulators of intracellular transduction signaling. Through a protein redox-sensor process, ROS can activate the MAPK pathway comprising MEK, ERK, p38 MAPK activities that, in turn, promote nuclear translocation of transcriptional factors including Jun, Fos, NRF2, NF-κB. These factors contribute to regulate several genes involved in antioxidant defenses (p53, NQO1, GSTs, SOD2, Ap-1, p53 and Prx I).

Figure 4

ROS-dependent therapeutic agents for leukemia treatment. The mechanism of action and the molecular targets of pro- or antioxidant drugs used in leukemia are shown. Along with conventional treatments, this figure depicts some promising examples of these approaches. 2-Methoxyestradiol (2ME2), a naturally occurring estrogen metabolite with antiproliferative and antiangiogenic activities is able to induce apoptosis through a ROS-dependent mechanism. Also, this drug is able to target LSCs by inhibiting the transcriptional activity of HIF-1α, that is found over-expressed in LSCs under hypoxic conditions, thus down-regulating pro-leukemic HIF-1α target genes, including the vascular endothelial growth factor (VEGF) [130,131]. L-asparaginase treatment has recently been reported to induce autophagy by promoting apoptosis and cell growth inhibition in AML cells and has synergistic effects with conventional AML chemotherapies [132]. The thiodioxopiperazine natural product chaetocin (SUV39H1 inhibitor) is a competitive substrate and inhibitor of thioredoxin reductase and in this way induces cellular oxidative stress. In addition, as inhibitor of SUV39H1, a co-factor of the transcription factor RUNX1 which has an important role in the regulation of proliferation and self-renewal of hematopoietic stem cells, chaetocin also promotes differentiation of AML cells and has synergistic effects with HDAC inhibitors [133,134]. Dotted arrows with question marks indicate plausible mechanisms of action. Full and dashed arrows indicate well-established or hypothetical molecular mechanisms, respectively.

Figure 5

Antioxidant and pro-oxidant strategies as antileukemia therapeutic tools. Pro-oxidant treatments are designed as a strategy to overwhelm the redox adaptation of leukemia cells by inducing oxidative stress incompatible with cellular viability. Enhanced ROS production leads to lipid peroxidation, protein oxidation and DNA damage resulting in increased apoptosis. Conversely, antioxidant treatments are aimed to reduce the leukemogenic potential by tuning down cell proliferation and survival pathways in leukemia cells with high ROS levels. Distinct arrows indicate the involvement of these treatments in different processes and subcellular compartments.