The significant role of redox system in myeloid leukemia: from pathogenesis to therapeutic applications

Abstract

Background Excessive generation of reactive oxygen species (ROS) in the presence of a defective antioxidant system can induce cellular damage and disrupt normal physiological functions. Several studies have revealed the unfavorable role of ROS in promoting the growth, proliferation, migration, and survival of leukemia cells. In this review study, we summarize the mechanisms of ROS production and its role in leukemogenesis, counteractive effects of antioxidants, and implicate the current ROS-dependent anticancer therapies in acute myeloid leukemia. Body The dysregulation of the redox system is known to play a significant role in the pathogenesis of leukemia. Leukemia cells generate high levels of ROS, which further increases the levels through extra pathways, including mitochondrial deoxyribonucleic mutation, leukemic oncogene activation, increased nicotinamide adenine phosphate hydrogen (NADPH), and cytochrome P450 activities. Aforementioned pathways once activated have shown to promote genomic instability, induce drug resistance to leukemia medical therapy, disease relapse and reduce survival period. The current standard of treatment with chemotherapy employs the pro-oxidant approach to induce apoptosis and promote tumor regression. However, this approach retains several deleterious effects on the subject resulting in degradation of the quality of life. Nevertheless, the addition of an antioxidant as an adjuvant drug to chemotherapy alleviates treatment-related toxicity, increases chemotherapeutic efficacy, and improves survival rates of a patient. Conclusion Acute myeloid leukemia remains a daunting challenge to clinicians. The desire to achieve the maximum benefit of chemotherapy but also improve patient outcomes is investigated. ROS generated through several pathways promotes leukemogenesis, drug resistance, and disease relapse. Chemotherapy, the mainstay of treatment, further upregulates ROS levels. Therefore, the addition of an antioxidant to leukemia medical therapy alleviates toxicity and improves patient outcomes.

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

“…Several mechanisms have been described as involved in aberrant ROS production in leukemia cells, including oncogene activation, mitochondrial disfunctions and metabolic changes. Furthermore, many antioxidant systems appear to be dysregulated, leading to increased overall ROS levels that allow cell survival without surpassing a deadly threshold, even under permanent oxidative stress [ 4 , 14 , 15 ]. On the other hand, ROS levels must be strictly regulated in normal and leukemic stem cells, thus underlining the importance of redox signaling to maintain cell stemness and control hematopoiesis and, in the meantime, unveiling the role of ROS as double-edged swords in leukemia.…”

“…More recently, other pro-oxidant strategies are being developed to modulate ROS levels either by inhibiting antioxidant defenses or by stimulating ROS release [ 19 , 116 , 117 ]. The pro-oxidant approach is based on the evidence that bulk AML cells are characterized by moderately higher oxidative stress state than their normal counterparts, almost in part related to enhanced antioxidant defenses that could drive drug resistance and confer a competitive advantage to the leukemic clone [ 15 ]. However, the accurate fine-tuning between ROS production and scavenging gives leukemia cells a higher sensitivity to external pro-oxidant stimuli that could lead to an unbearable situation of oxidative stress incompatible with cell viability [ 82 ].…”

“…Notably, in AML cells high ROS levels are compensated for by robust antioxidant systems to avoid excessive ROS production and to protect leukemic cells from oxidative stress-induced cell death [ 13 , 14 ]. Anyway, given their high rate of ROS production, AML cells have a lower buffering capacity against ROS disruption that make them more sensitive to pro-oxidant treatments than their normal counterpart [ 15 ].…”

Increased Oxidative Stress in Acute Myeloid Leukemia Patients after Red Blood Cell Transfusion, but Not Platelet Transfusion, Results Mainly from the Oxidative/Nitrative Protein Damage: An Exploratory Study

“…The excessive production of ROS in leukemia cells has been well documented, although the underlying mechanisms are not clearly defined [ 7 , 25 ]. Based on our results, an increase in OS was confirmed in AML patients compared to healthy volunteers.…”

“…Evidence for chronic OS, caused by the increased production of reactive oxygen/reactive nitrogen species (ROS/RNS) and/or depletion of the antioxidant defense systems, has been found in several hematopoietic malignancies including AML [ 7 , 8 ]. Some reports indicate that relapse in this disease is associated with increased OS markers within the leukemic blasts, suggesting that ROS production may be an important factor of AML progression [ 8 ].…”