Iron Oxide Nanoparticles Combined with Cytosine Arabinoside Show Anti-Leukemia Stem Cell Effects on Acute Myeloid Leukemia by Regulating Reactive Oxygen Species

Abstract

Background and Aim Acute myeloid leukemia (AML), initiated and maintained by leukemia stem cells (LSCs), is often relapsed or refractory to therapy. The present study aimed at assessing the effects of nanozyme-like Fe 3 O 4 nanoparticles (IONPs) combined with cytosine arabinoside (Ara-C) on LSCs in vitro and in vivo. Methods The CD34 + CD38 – LSCs, isolated from human AML cell line KG1a by a magnetic activated cell sorting method, were treated with Ara-C, IONPs, and Ara-C+ IONPs respectively in vitro. The cellular proliferation, apoptosis, reactive oxygen species (ROS), and the related molecular expression levels in LSCs were analyzed using flow cytometry, RT-qPCR, and Western blot. The nonobese diabetic/severe combined immune deficiency mice were transplanted with LSCs or non-LSCs via tail vein, and then the mice were treated with Ara-C, IONPs and IONPs plus Ara-C, respectively. The therapeutic effects on the AML bearing mice were further evaluated. Results LSCs indicated stronger cellular proliferation, more clone formation, and more robust resistance to Ara-C than non-LSCs. Compared with LSCs treated with Ara-C alone, LSCs treated with IONPs plus Ara-C showed a significant increase in apoptosis and ROS levels that might be regulated by nanozyme-like IONPs via improving the expression of pro-oxidation molecule gp91-phox but decreasing the expression of antioxidation molecule superoxide dismutase 1. The in vivo results suggested that, compared with the AML bearing mice treated with Ara-C alone, the mice treated with IONPs plus Ara-C markedly reduced the abnormal leukocyte numbers in peripheral blood and bone marrow and significantly extended the survival of AML bearing mice. Conclusion IONPs combined with Ara-C showed the effectiveness on reducing AML burden in the mice engrafted with LSCs and extending mouse survival by increasing LSC’s ROS level to induce LSC apoptosis. Our findings suggest that targeting LSCs could control the AML relapse by using IONPs plus Ara-C.

Ferric oxide nanoparticles administration suppresses isoniazid induced oxidative stress in the rat brain tissue

“…In recent years, nanoparticles are known as novel antioxidants that protect against some oxidative stress damage [43]. Metal-based nanoparticles including iron oxide have beneficial roles in management of diseases regarding their antioxidant effects [44,45]. In the present study the antioxidant role of ferric oxide nanoparticles against isoniazid induced neurotoxicity was studied via the evaluation of several markers of the oxidative stress.…”

Eltrombopag and its iron chelating properties in pediatric acute myeloid leukemia

“…Even though acute myeloid leukemia (AML) principally affects elderly [ 2 ], it represents the 20% of childhood leukemia cases [ 1 ]. The most relevant aspect of pediatric AML remains the poor prognosis [ 26 ] with a long-term survival rate around the 50% [ 27 ], when patients are properly treated.…”

“…Acute myeloid leukemia (AML) represents the 20% of total childhood leukemia diagnoses [ 1 ], even though it remains the most frequent type of acute leukemia in the elderly [ 2 ]. In 0–2 year-old children, this kind of leukemia is characterized by poor prognosis, with a survival rate around the 60% [ 3 ], and high treatment-related toxicity [ 4 ].…”

Application of iron oxide nanoparticles in the diagnosis and treatment of leukemia

“… Dou et al (2021) found that the combination of Fe 3 O 4 nanoparticles with cytarabine (Ara-C) inhibited leukemia stem cell (LSC) more than Ara-C alone. They analyzed changes in ROS-related substances such as gp91-phox and SOD1 by measuring ROS levels in LSC and non-LSC under different conditions.…”