Targeting the MAPK/ERK and PI3K/AKT Signaling Pathways Affects NRF2, Trx and GSH Antioxidant Systems in Leukemia Cells

Abstract

The mitogen-activated protein kinase (MAPK)/extracellular signal kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signal transduction pathways have been implicated in the pathogenesis of leukemia. The aim of this study was to investigate the effect of the combination of ERK1/2 inhibitor AZD0364 and PI3K inhibitor ZSTK474 on acute lymphoblastic leukemia (ALL) REH, MOLT-4, acute myeloid leukemia (AML) MOLM-14, and chronic myeloid leukemia (CML) K562 cell lines. To evaluate the interactions of the drugs, cells were treated for 48 h with AZD0364 or ZSTK474 alone and in combination at fixed ratios. The combinatorial effects of both inhibitors were synergistic over a wide range of concentrations in REH, MOLT-4, and MOLM-14 cell lines. However, in K562 cells, the effects were found to be antagonistic. Furthermore, AZD0364 and ZSTK474 significantly decreased both ERK1/2 and AKT activation in REH, MOLT-4, and MOLM-14 cells. The results showed that incubation with both AZD0364 and ZSTK474 inhibited cell viability, increased reactive oxygen species (ROS) production, and induced apoptosis in leukemia cells. We observed that combined treatment with AZD0364 and ZSTK474 affected nuclear factor-κB (NF-κB) and antioxidant protein levels: NF-E2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), thioredoxin (Trx), thioredoxin reductase (TrxR), and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio. These effects were accompanied with decreased antiapoptotic survivin protein level. However, distinct cell line dependent effects were observed. In conclusion, the combination of AZD0364 and ZSTK474 can exert a synergistic anticancer effect in ALL and AML cells, which is associated with the induction of oxidative stress and the involvement of cellular antioxidant defense mechanisms.

Tomentosin inhibits cell proliferation and induces apoptosis in MOLT‐4 leukemia cancer cells through the inhibition of mTOR/PI3K/Akt signaling pathway

“…Comparatively, a recent study reported several plant‐based bioactive molecules such as caffeic acid and chrysophanol that exert their anticancer effects through inhibition of cell proliferation. [ 14,15 ]…”

“…Comparatively, a recent study reported several plant-based bioactive molecules such as caffeic acid and chrysophanol that exert their anticancer effects through inhibition of cell proliferation. [14,15] It is reported that most of the cytotoxic agents stimulate apoptosis. ROS, which are largely yielded by the mitochondria, under pathological condition, may be excessively produced.…”

Aldo-Keto Reductase 1C3 Mediates Chemotherapy Resistance in Esophageal Adenocarcinoma via ROS Detoxification

“…PTPs could dephosphorylate insulin receptor substrate protein 1 (IRS-1) in response to insulin-induced ROS and activate PI3K/AKT pathway subsequently, which plays a significant role in chemotherapy resistance [ 56 ]. Activation of the PI3K/AKT signaling pathway has been shown to be essential in modulating glutathione metabolism [ 57 ]. Besides, the activation of AKT is crucial in the regulation of GSH synthesis [ 57 , 58 , 59 ].…”

“…Activation of the PI3K/AKT signaling pathway has been shown to be essential in modulating glutathione metabolism [ 57 ]. Besides, the activation of AKT is crucial in the regulation of GSH synthesis [ 57 , 58 , 59 ]. Kim et al revealed that the AKT/p70S6K pathway was capable of manipulating the GSH biosynthesis activated by insulin [ 60 ].…”

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

“…However, Notch also downregulates the expression of protein kinase C θ (PKC-θ) through the runt-related transcription factor (RUNX) pathway, thereby inhibiting intracellular ROS accumulation and facilitating the maintenance of LIC activity [ 100 ]. In addition, numerous studies have shown that various antioxidant proteins, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), also have important regulatory roles in the antioxidant responses of ALL cells [ 111 , 112 ].…”