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.

Keywords: Acute myeloid leukemia; Antioxidants; Jab1/COPS5; Oncogene mutations; Oxidative stress; Reactive oxygen species.

Fig. 1

The different mechanisms of ROS generation in leukemia cells and their role in leukemogenesis. (1) MtDNA mutations lead to alternations in the mtETC, resulting in increased ROS production promoting DNA damage, genomic instability, and drug resistance in AML. (2) Activated genetic polymorphisms of CYP450 in AML, ALL, and CLL, generate high ROS levels contributing to cell proliferation, survival, drug resistance, and disease relapse. (3) Elevated XO/XDH activity leads to increased ROS & OS attributed to AML relapse and progression. (4) Leukemic oncogene activity (BCR/ABL, Flt3-ITD, Ras, c-Kit, JAK2 V617F) induce NADPH elevation and increased NOX activity resulting in elevated ROS levels which promote DNA damage, genetic instability, proliferation, survival, migration, and drug resistance in leukemic cells. (5) Increased ROS generated from leukemic cells, oncogene mutations, abnormal metabolism with an ineffective antioxidant system results in increased OS which aberrantly expresses Jab1/COPS5 leading to AML proliferation, progression, and relapse. Abbreviations: mitochondrial ETC, electron transport chain; CYP450, cytochrome P450; XO, xanthine oxidase; XDH, xanthine dehydrogenase; AML, acute myeloid leukemia; BCR/ABL, Breakpoint cluster region-Abelson leukemia virus; Flt3-FTD, FMS-like tyrosine kinase 3-internal tandem duplication; c-Kit, receptor tyrosine kinase; JAK2 V617F, Janus kinase 2 V617F; Jab1/COPS5, c-Jun activation domain-binding protein-1

Fig. 2

Mechanisms by which the pro-oxidant approach induces cell death in leukemia treatment

Fig. 3

Mechanisms by which antioxidants counteract deleterious effects of pro-oxidant therapy. Antioxidant application to pro-oxidant therapy reduces OS, ROS signaling, and proliferative drive. Furthermore, it induces cell cycle suppression, increases tumor response of AML cells, and protects nonmalignant cells