Oxidative Stress and Chronic Myeloid Leukemia: A Balance between ROS-Mediated Pro- and Anti-Apoptotic Effects of Tyrosine Kinase Inhibitors

Abstract

The balanced reciprocal translocation t (9; 22) (q34; q11) and the BCR-ABL fusion gene, which produce p210 bcr-abl protein production with high tyrosine kinase activity, are characteristics of chronic myeloid leukemia, a myeloproliferative neoplasm. This aberrant protein affects several signaling pathways connected to both apoptosis and cell proliferation. It has been demonstrated that tyrosine kinase inhibitor treatment in chronic myeloid leukemia acts by inducing oxidative stress and, depending on its level, can activate signaling pathways responsible for either apoptosis or survival in leukemic cells. Additionally, oxidative stress and reactive oxygen species generation also mediate apoptosis through genomic activation. Furthermore, it was shown that oxidative stress has a role in both BCR-ABL-independent and BCR-ABL-dependent resistance pathways to tyrosine kinases, while patients with chronic myeloid leukemia were found to have a significantly reduced antioxidant level. The ideal environment for tyrosine kinase inhibitor therapy is produced by a favorable oxidative status. We discuss the latest studies that aim to manipulate the redox system to alter the apoptosis of cancerous cells.

Keywords: BCR-ABL1; RNA interference; apoptosis; chemoresistance; chronic myeloid leukemia; fenretinide; nanoparticles; oxidative stress; reactive oxygen species; tyrosine kinase inhibitors.

Figure 1

ROS are directly implicated in apoptotic dynamics since they may encourage genomic instability and may facilitate the apoptosis of leukemic cells. Both intrinsic and extrinsic pathways are involved in apoptosis via the effects on caspases, Calpains, and aptosome. While the extrinsic pathway is dependent on cell-surface death receptors such as Fas (First apoptosis signal), the intrinsic pathway is initiated within mitochondria. BID BH3 interacting-domain death agonist; Mcl-1 myeloid leukemia cell differentiation protein; IAP1 inhibitor of apoptosis 1; BH3 Bcl-2 homology domain 3.

Figure 2

Possible mechanisms of dasatinib-mediated apoptosis. Dasatinib increases the concentration of ROS, reduces the intracellular glutathione content (GSH), reduces the activity of superoxide dismutase (SOD), causes lipid peroxidation producing malondialdehyde (MDA), decreases the mitochondrial membrane potential, and activates nuclear factor erythroid 2-related factor 2 (Nrf2) and mitogen-activated protein kinases (MAPK) related to oxidative stress.

Figure 3

Possible adjuvant role of small interference RNA (siRNA) (A) and ultraviolet radiation (B) in the treatment of patients affected by CML who have developed resistance to imatinib.