Oxidative resistance of leukemic stem cells and oxidative damage to hematopoietic stem cells under pro-oxidative therapy

Abstract

Leukemic stem cells (LSCs) and hematopoietic stem cells (HSCs) are both dependent on the hypoxic bone marrow (BM) microenvironment (also known as the BM niche). There is always fierce competition between the two types of cells, and the former exhibits a greater competitive advantage than the latter via multiple mechanisms. Under hypoxia, the dynamic balance between the generation and clearing of intracellular reactive oxygen species (ROS) is conducive to maintaining a quiescent state of cells. Quiescent LSCs can reside well in the BM niche, avoiding attack by chemotherapeutic agents, which is the cause of chemotherapeutic resistance and relapse in leukemia. HSCs acquire energy mainly through anaerobic glycolysis, whereas LSCs achieve energy metabolism largely through mitochondrial oxidative respiration. Mitochondria are the primary site of ROS generation. Thus, in theory, mitochondria-mediated respiration will cause an increase in ROS generation in LSCs and a higher intracellular oxidative stress level. The sensitivity of the cells to pro-oxidant drugs increases as well, which allows for the selective clearing of LSCs by prooxidative therapy. However, HSCs are also highly sensitive to changes in ROS levels, and the toxic effects of prooxidant drugs on HSCs poses a major challenge to pro-oxidative therapy in leukemia. Given the above facts, we reviewed studies on the oxidative resistance of LSCs and the oxidative damage to HSCs under pro-oxidative therapy. An in-depth investigation into the oxidative stress status and regulatory mechanisms of LSCs and HSCs in hypoxic environments will promote our understanding of the survival strategy employed by LSCs and the mechanism of the oxidative damage to HSCs in the BM niche, thus facilitating individualized treatment of leukemia patients and helping eliminate LSCs without disturbing normal hematopoietic cells.

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

“…Furthermore, HSCs and LSCs significantly differ in their metabolic pathways. In fact, whereas HSCs mainly rely on glycolysis, LSCs depend on oxidative metabolism for their survival [ 18 , 19 ]. As a whole, these disturbed pathways confer drug resistance capabilities on LSCs that make them more resistant to chemotherapies [ 20 , 21 ].Therefore, there is urgent need of identifying novel therapies more effective in targeting quiescent, chemotherapy resistant LSCs to eradicate AML residual disease.…”

Development of Multidrug Resistance in Acute Myeloid Leukemia Is Associated with Alterations of the LPHN1/GAL-9/TIM-3 Signaling Pathway

“…However, a serious complication of AML chemotherapy is the development of chemoresistance [ 17 ], particularly the resistant nature of leukemic stem cells capable of reconstituting the disease during remission and causing relapse of AML [ 49 ]. Chemoresistance, especially multidrug resistance, is a phenotype caused by complex molecular functions that affect a wide range of cellular regulatory and metabolic mechanisms.…”

Redox Control in Acute Lymphoblastic Leukemia: From Physiology to Pathology and Therapeutic Opportunities

“…Among them, HIF-1 is a key factor regulating the cellular hypoxia response. Under hypoxic conditions, HIF-1 regulates the transcription of a variety of hypoxia-responsive genes and participates in hypoxia adaptation, angiogenesis, immune responses, and apoptosis [ 45 , 46 ]. HIF-1 consists of a constitutively expressed subunit (HIF-1β) and an inducible subunit (HIF-1α) that is stabilized under hypoxic conditions.…”

“…Extracellularly, ALL cells establish extensive contact with the BM niche via chemokines, adhesion molecules, and exosomes and transform the BM niche into a leukemia growth-permissive and normal hematopoiesis-suppressive leukemia niche to improve the survival of ALL cells in a hypoxic environment [ 46 ]. Under oxidative stress conditions, BMSCs produce protective soluble factors, which help ALL cells achieve redox adaptation and reduce oxidative stress damage, ultimately inducing the reversible multidrug resistance phenotype in ALL cells [ 5 ].…”