Glutathione in metastases: From mechanisms to clinical applications

Abstract

Metastatic spread, not primary tumors, is the leading cause of cancer death. Glutathione (γ-glutamyl-cysteinyl-glycine, GSH) is particularly relevant in cancer cells as it is involved in regulating carcinogenic mechanisms, growth and dissemination, and multidrug and radiation resistance. Upon interaction of metastatic cells with the vascular endothelium, a high percentage of metastatic cells with high GSH levels survive the combined nitrosative and oxidative stresses elicited by the vascular endothelium. GSH release from different organs, mainly the liver, and its interorgan transport through the blood circulation to metastatic foci, promote their growth. This review focuses on the relationship among GSH and different key mechanisms that facilitate metastatic cell survival and growth, i.e. adaptive responses to stress, cell death evasion and utilization of physiological neuroendocrine mechanisms. Different strategies that are aimed at sensitizing metastases to cancer therapy by depleting metastatic cell GSH are analyzed.

Methionine Restriction and Cancer Biology

“…Despite the MR-induced reduction in hepatic GSH, MR does not increase oxidative stress, in part because MR enhances antioxidant capacity and increases proton leak in the liver, likely decreasing ROS production [51]. The ability of MR to increase GSH levels in red blood cells is significant because of the role of GSH in the neutralization of ROS [52]. Several animal studies have shown restricting dietary methionine by just 40% reduces mitochondrial ROS production in several tissues, resulting in reduced mitochondrial DNA oxidative damage in vivo [30,53,54].…”

Supramolecules‐Guided Synthesis of Brightly Near‐Infrared Au22 Nanoclusters with Aggregation‐Induced Emission for Bioimaging

“…Our results show that both BSA‐AuNCs and AuNCs@PAH do not affect cell viability at concentrations up to 0.6 mg mL −1 ( Figure a). It was reported recently that a high percentage of metastatic cells with high GSH levels survived under the combined nitrosative and oxidative stresses elicited by the vascular endothelium, and GSH level in lung tumors ranged from 0.5 to 3 m m , while GSH level in normal lung tissue was four times lower . Hence the difference in GSH concentration in healthy and tumorigenic tissues could be used to image the location of tumors by detecting the change of PL intensity of AuNCs.…”

Toxicity mechanism-based prodrugs: glutathione-dependent bioactivation as a strategy for anticancer prodrug design

“…To avoid the detrimental effects of ROS, cancer cells actively upregulate multiple antioxidant systems [58,80,83,84]. As a result, many cancer cells contain high GSH concentrations and overexpress the related enzymes, such as GGT [20] and GST [64,85]; high GSH concentrations are generally beneficial to initiation, progression, and metastasis of cancers [13,78,79,84,86,87]. Multidrug and radiation resistance of many tumors appears to be associated with higher GSH levels and/or lower ROS levels in the cancer cells [13,58,86,88].…”

“…As a result, many cancer cells contain high GSH concentrations and overexpress the related enzymes, such as GGT [20] and GST [64,85]; high GSH concentrations are generally beneficial to initiation, progression, and metastasis of cancers [13,78,79,84,86,87]. Multidrug and radiation resistance of many tumors appears to be associated with higher GSH levels and/or lower ROS levels in the cancer cells [13,58,86,88]. Consequently, it has been proposed that cancer patients should be treated with pro-oxidants that exacerbate oxidative stress or block metabolic adaptations that confer oxidative stress resistance [78,80,89].…”