Long‐Term Alteration of Reactive Oxygen Species Led to Multidrug Resistance in MCF‐7 Cells

Abstract

Reactive oxygen species (ROS) play an important role in multidrug resistance (MDR). This study aimed to investigate the effects of long-term ROS alteration on MDR in MCF-7 cells and to explore its underlying mechanism. Our study showed both long-term treatments of H2O2 and glutathione (GSH) led to MDR with suppressed iROS levels in MCF-7 cells. Moreover, the MDR cells induced by 0.1 μM H2O2 treatment for 20 weeks (MCF-7/ROS cells) had a higher viability and proliferative ability than the control MCF-7 cells. MCF-7/ROS cells also showed higher activity or content of intracellular antioxidants like glutathione peroxidase (GPx), GSH, superoxide dismutase (SOD), and catalase (CAT). Importantly, MCF-7/ROS cells were characterized by overexpression of MDR-related protein 1 (MRP1) and P-glycoprotein (P-gp), as well as their regulators NF-E2-related factor 2 (Nrf2), hypoxia-inducible factor 1 (HIF-1α), and the activation of PI3K/Akt pathway in upstream. Moreover, several typical MDR mediators, including glutathione S-transferase-π (GST-π) and c-Myc and Protein Kinase Cα (PKCα), were also found to be upregulated in MCF-7/ROS cells. Collectively, our results suggest that ROS may be critical in the generation of MDR, which may provide new insights into understanding of mechanisms of MDR.

Triterpenoids fromAglaia abbreviataexert cytotoxicity and multidrug resistant reversal effect in MCF-7/ADM cells via reactive oxygen species induction and P-glycoprotein inhibition

“…High level of ROS was usually proposed as the cell-damaging factors of chemotherapy [ 19 ], while sustained and moderate production of ROS in MDR cells exhibited signal effects to activate survival signaling pathways such as the PI3K/Akt pathway, which facilitates oncogenic phenotype of cancer [ 20 , 21 ]. Consistently, our study demonstrated higher levels of basal intracellular ROS and activities of the Akt pathway in MDR cells than their sensitive counterparts ([ 10 ] and Figure 3A ). Treatments of AA-5 (1) and AA-6 (2) for 48 h significantly increased the level of ROS (Figure 2B ), and co-treatment with NAC greatly restored the AAs-decreased p-Akt expression (Figure 3A ).…”

“…Nrf2 mediates anti-oxidative response as a transcription factor. And Nrf2-activated cytoprotective genes include heme oxygenase-1 (HO-1), glutathione S-transferase (GST), and P-gp [ 9 , 10 ]. Therefore, constitutive Nrf2 activation is recognized to be responsible for chemoresistance in tumors [ 8 ].…”

Nrf2 overexpression protects against paraquat‑induced A549 cell injury primarily by upregulating P‑glycoprotein and reducing intracellular paraquat accumulation

“…The primary focus of research on Nrf2 targets has been on detoxifying/antioxidant enzymes; however, several ABC transporters are Nrf2 targets (25). Furthermore, previous studies have revealed that the activation of Nrf2 is necessary to increase P-gp activity (26–28). Therefore, the current study hypothesized that Nrf2 may prevent organ injury in PQ poisoning by increasing P-gp activation and reducing intracellular PQ concentration.…”

Metabolic Reprogramming During Multidrug Resistance in Leukemias

“…Notwithstanding, the effect of ROS as agents of oxidative stress affecting the expression of ABCB1 is controversial. Both, downregulation and upregulation of the transporter have been reported ( 24 , 25 ). Antioxidants ( 26 ), as well as products resulting from glycolysis can act as scavengers of free radicals.…”