Relationship of oxidative stress in the resistance to imatinib in Tunisian patients with chronic myeloid leukemia: A retrospective study

Abstract

Background This work aimed to evaluate oxidative stress in chronic myeloid leukemia (CML) patients treated with tunisian (IM) vs controls and in CML patients with resistance to IM vs patients without resistance to IM. Methods The study included 40 CML patients and 34 controls. Of 40 patients with CML, 26 patients were developed in resistance to IM. The oxidant/antioxidant markers were evaluated by spectrophotometric methods for all used samples. Results For CML patients, increased malondialdehyde (MDA) and advanced oxidation protein products (AOPP) levels were found compared to controls (P < .001; P = .01). Higher catalase (CAT) activity (P = .048) and lower superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, reduced Glutathione (GSH) and vitamin C levels were found in CML patients (P < .001). The comparison between the resistant vs no‐resistant CML patients revealed higher MDA level (P = .02) and CAT and SOD activities in IM‐resistant patients (P = .04, P = .03). GPx activity was reduced (P = .04). Furthermore, increased mean ratio of MDA/GSH, MDA/GPx, and SOD/(GPx + CAT) was found in IM‐resistant patients as compared with no‐resistant (P = .01, P = .01, P = .035). The mean ratio of GPx/GSH in the IM‐resistant CML patients was lower than in IM no‐resistant one (P = .039). For IM‐resistant patients, we found negative correlation between MDA level and the ratio SOD/(CAT + GPx) (r = −0.46, P = .002); and positive correlation between SOD and (CAT + GPx) activities (r = 0.38, P = .06) and between GSH level and GPx activity (r = 0.53, P = .01). Conclusions Our results have shown a highly disturbed oxidative profile in IM‐resistant CML patients as compared to no‐resistant. The H2O2 has a key role in the resistance to IM treatment.

Oxidative stress in leukemia and antioxidant treatment

“…Exogenous ROS is mainly caused by exogenous substances, such as radiation and drugs; whereas endogenous ROS is the products of intracellular aerobic metabolism, among which the mitochondrial electron transport system and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex are the primary sources. [ 5 ] Meanwhile, to protect cells from oxidative damage, aerobic organisms also have an antioxidant defense system. The excessive production of ROS intermediates, exceeding the functional capacity of cellular antioxidants, may lead to the instability of important macromolecules, which is the molecular basis of inflammatory processes, cardiovascular diseases, cancer, and other diseases.…”

“…[ 7 ] It can stimulate ribosylation of poly adenosine diphosphate (ADP) of chromosome proteins, further to induce kinases activation, gene mutations, chromosome DNA degeneration, mitochondrial membrane potential changes, pro-apoptotic proteins activation and translocation, and anti-apoptotic proteins down-regulation, thus promoting carcinogenesis. [ 5 ] In conclusion, oxidative stress involves the process of oncogenesis and progression in cancers.…”

“…However, high levels of ROS or continuous oxidative stress can cause severe damage to HSCs, thus altering their metabolic state and then incapacitating them. [ 5 ] ROS causes changes in the hematopoietic microenvironment, which in turn causes senescence or apoptosis of HSCs. Because HSCs that survive in niches have lower ROS levels than other general tissues, they are very sensitive to changes in ROS levels and gene mutations.…”

“…[ 64 ] HO-1, a cytoprotective protein in the heme oxygenase (HO) family, potentially plays a key role in oxidative stress and inhibits apoptosis of AML cells by activating the JNK/c-Jun signaling pathway. [ 5 ] HO-1 gene can be transcribed by Nrf2 , usually occurring after oxidative stress and cell injury. HO-1 can reduce oxidative stress and inflammation, protect cells from apoptosis, and alter cell cycle, thus improving the prognosis of patients with leukemia.…”

“…It can activate some tumor suppressor genes, such as NF-κB and p53 by increasing the production of ROS, leading to apoptosis of leukemic cells. [ 5 ] Piprartin can inhibit the proliferation and survival of different kinds of leukemia cells. It can inhibit the proliferation of B-cell acute lymphocytic leukemia cells without affecting normal B-cells, which is achieved by increasing ROS-induced apoptosis.…”