Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity

Abstract

O(2)(-) is an important mediator of 2-ME-induced apoptosis. The increased oxidative stress in cancer cells forces these cells to rely more on antioxidant enzymes such as SOD for O(2)(-) elimination, thus making the malignant cells more vulnerable to SOD inhibition than normal cells.

NQO1-activated phenothiazinium redox cyclers for the targeted bioreductive induction of cancer cell apoptosis

“…Thus, constitutively elevated levels of cellular oxidative stress and dependence on ROS-signaling may represent a redox vulnerability of malignancy that can be targeted by chemotherapeutic intervention using redox modulators, and both anti-and prooxidant agents have been shown to exert anti-cancer activity. According to this hypothesis, pro-oxidant pharmacological agents that substantially increase cellular ROS would induce deviations from redox homeostasis that do not reduce viability of untransformed cells, but cannot be tolerated by malignant cells that are already under high constitutive oxidative stress [1,12]. Indeed, prooxidant redox agents including metal-based drugs such as dithiocarbamate chelates [13] and therapeutics in advanced clinical development such as texaphyrins [14] can achieve cancer cell-selective cytotoxicity [15,16].…”

Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism

“…17 To ensure the consistency of the assay conditions for patient samples at different days, we used a reference cell line (Raji cells) stained under identical conditions as a control for comparable parameter settings. 13 …”

“…[7][8][9] Compared with normal lymphocytes, CLL cells were shown to display a substantial increase in ROS associated with oxidative DNA damage and mitochondrial DNA (mtDNA) mutations, especially in patients who had undergone prior therapy with DNA-damaging agents. [10][11][12][13] Because mitochondrial respiratory chain is the major site of ROS generation due to electron bifurcation from the transport complexes, it is conceivable that dysfunction of mitochondrial respiration would increase electron leakage and lead to elevated ROS generation. Interestingly, the loss of p53 seems to promote mtDNA mutations and enhance ROS production in cultured cell lines.…”

Improved Catalytic Activity of Ruthenium–Arene Complexes in the Reduction of NAD+

“…On the one hand, due to their active metabolism, cancer cells generate high levels of oxidizing species and, therefore, they are under constant oxidative stress. 4 This makes cancer cells more dependent on redox regulatory systems and more sensitive to variations in the NAD + /NADH ratio. On the other hand, NAD + is required as a substrate for many enzymatic reactions such as ADP-ribosylation, which is crucial for genome stability and DNA repair.…”

“…3 Due to the up-regulation of some enzymes required for the biosynthesis of NAD + in cancer cells, a decrease in the NAD + concentration can cause apoptosis of cancer cells while having little effect on normal cells. 4 From an industrial perspective, NADH regeneration is an important process due to its high applicability in chiral organic synthesis and biocatalysis. The coenzymes, for instance, are required as substrates for many enzymatic reactions used for stereoselective synthesis, such as formation of D-lactate from pyruvate or chiral alcohols by alcohol dehydrogenases.…”