Targeting Redox Metabolism in Pancreatic Cancer

Abstract

Cell metabolism is reprogrammed in cancer cells to meet their high bioenergetics and biosynthetic demands. This metabolic reprogramming is accompanied by alterations in redox metabolism, characterized by accumulation of reactive oxygen species (ROS). Elevated production of ROS, mostly by mitochondrial respiration, is counteracted by higher production of antioxidant defenses (mainly glutathione and antioxidant enzymes). Cancer cells are adapted to a high concentration of ROS, which contributes to tumorigenesis, metastasis formation, resistance to therapy and relapse. Frequent genetic alterations observed in pancreatic ductal adenocarcinoma (PDAC) affect KRAS and p53 proteins, which have a role in ROS production and control, respectively. These observations led to the proposal of the use of antioxidants to prevent PDAC development and relapse. In this review, we focus on the therapeutic strategies to further increase ROS level to induce PDAC cell death. Combining the promotion of ROS production and inhibition of antioxidant capacity is a promising avenue for pancreatic cancer therapy in the clinic.

Synthesis, Characterization and Antitumor Mechanism Investigation of Heterometallic Ru(Ⅱ)-Re(Ⅰ) Complexes

“…Herein, cells were treated with RuRe-1 and RuRe-2 for 6 h and then stained with 2′,7′-dichlorodihydrouorescein diacetate (H 2 DCFDA). H 2 DCFDA is non-fluorescent and can be oxidized by intracellular ROS to highly fluorescent 2′,7′-dichlorofluorescein (DCF) ( Abdel Hadi et al, 2021 ). The intensity of green fluorescence can respond to the accumulation of intracellular ROS.…”

The expression and survival significance of sodium glucose transporters in pancreatic cancer

“…Current “ROS threshold” theories suggest that along with increases in ROS, cell responses change from proliferation to balance and then to cell death after ROS surpass a certain level [ 45 ]. Mild-to-moderate levels of ROS are associated with the activation of protomourigenic survival and growth pathways, while excessive concentrations of ROS can lead to the induction of cell cycle arrest and cell death [ 20 , 25 , 26 ]. In accordance with this, it has been reported that higher expression of MAP17 and SGLT-1 was correlated with better prognosis in laryngeal and cervical cancers [ 10 , 11 ].…”

“…Notably, it could stimulate the specific Na-dependent transportation of mannose and glucose in Xenopus oocytes and human tumour cells and was overexpressed in a variety of human carcinomas, enhancing the tumorigenic phenotype by increasing intracellular ROS [ 12 , 14 – 19 ]. ROS are oxygen-derived molecules, mostly the free radicals superoxide anion O 2 − and hydroxyl radical -OH, and they can promote cancer development, chemoresistance, and relapse by causing oxidative DNA damage and genomic instability and modifying gene expression [ 20 – 23 ]. It has been reported that the levels of ROS are notably increased in patients with pancreatic cancer and are involved in the progression, drug resistance, recurrence and metastasis of pancreatic cancer [ 24 , 25 ].…”

Dietary Iron Overload and Hfe−/− Related Hemochromatosis Alter Hepatic Mitochondrial Function

“…Of note, Hfe −/− mice on ND showed increased mitochondrial superoxide production, even without additional dietary iron loading. This might have been caused by the elevation in mitochondrial respiratory capacity as Complexes I and III are able to produce increased radical amounts [59].…”