Glutathione: Lights and Shadows in Cancer Patients

Abstract

In cases of cellular injury, there is an observed increase in the production of reactive oxygen species (ROS). When this production becomes excessive, it can result in various conditions, including cancerogenesis. Glutathione (GSH), the most abundant thiol-containing antioxidant, is fundamental to re-establishing redox homeostasis. In order to evaluate the role of GSH and its antioxi-dant effects in patients affected by cancer, we performed a thorough search on Medline and EMBASE databases for relevant clinical and/or preclinical studies, with particular regard to diet, toxicities, and pharmacological processes. The conjugation of GSH with xenobiotics, including anti-cancer drugs, can result in either of two effects: xenobiotics may lose their harmful effects, or GSH conjugation may enhance their toxicity by inducing bioactivation. While being an interesting weapon against chemotherapy-induced toxicities, GSH may also have a potential protective role for cancer cells. New studies are necessary to better explain the relationship between GSH and cancer. Although self-prescribed glutathione (GSH) implementation is prevalent among cancer patients with the intention of reducing the toxic effects of anticancer treatments and potentially preventing damage to normal tissues, this belief lacks substantial scientific evidence for its efficacy in reducing toxicity, except in the case of cisplatin-related neurotoxicity. Therefore, the use of GSH should only be considered under medical supervision, taking into account the appropriate timing and setting.

Keywords: antioxidants; cancer; chemotherapy; diet; glutathione; nutraceuticals; toxicity.

Figure 1

PRISMA diagram [3].

Figure 2

(A) Biosynthetic pathway and antioxidant role of GSH and its interconversion into the oxidized form GSSG. (B) Intracellular distribution, degradation pathways, and recycling of GSH. GSH = glutathione; N = nucleus; M = mitochondrion; ER = endoplasmic reticulum; Gln = glutamine; Glu = glutamic acid; Cys = cysteine; Gly = glycine; Gly T = glycine transporter; Xc- = cystine/glutamate antiporter; ASCT2 = Alanine/serine/cysteine transporter 2; GLS = glutaminase; γ-GC = γ -glutamyl-cysteine; GCL = glutamate-cysteine ligase; GS = glutathione-synthetase; GPx = glutathione peroxidase; GSSG = glutathione disulfide; GR = glutathione reductase; Cys-Gly = cysteine–glycine; ASC = Alanine/serine/cysteine transporter 1; MRP1 = multidrug-resistant protein 1; GSTs = glutathione S-transferases; Xen = xenobiotics; GSH-Xen = glutathione plus xenobiotics; γ-GT = γ-glutamyl transferase; DP = Cysteinyl glycine dipeptidase; ChaC = glutathione-specific gamma-glutamylcyclotransferase; CGp = Cys-Gly peptidase; 5 oxo = 5-oxoprolinase.

Figure 3

Bioactive compounds from diet able to interfere on cancer cells by modulating circulating GSH levels. Amino acids: see references [40,41,42]; omega-3 fatty acids: see references [43,44]; selenium-vitamins: see references [45,46,47,48,49,50,51,52,53,54,55,56,57,58]; phytochemicals: see references [59,60,61,62,63,64,65,66]; green tea: see references [67,68,69]; fruit-vegetables juices: see references [70,71,72,73,74,75,76,77,78].

Figure 4

A rational use of GSH in cancer patients should not overlook an ideal and minimal evaluation of the enzymatic triad involved in GSH synthesis and metabolism (see polymorphisms, expression, and epigenetic control discussed in the manuscript). Indeed, there may be different activity levels of the enzymatic triad in the patient and the tumor, with indirectly assessable effects. When one of the enzymes has reduced activity, it affects the overall GSH production balance, leading to a decrease in its concentration (and corresponding antioxidant power). The scenario where there is reduced activity in cancer patients, in general, may be associated with increased chemotherapy efficacy, albeit at the cost of greater toxicity for the patient (A). In cases where the enzymatic triad functions well in healthy cells but is impaired in the tumor cells, it represents a positive scenario where chemotherapy can have a greater damaging effect on the neoplasm. However, as shown in the last panel (B), this is not true for all drugs. It would be desirable to further investigate the biology of cancer regarding these aspects, especially when the enzymatic triad is “overactive” only in the tumor. Such an approach could lead to the pharmacological design of specific inhibitors targeting the tumor enzymes involved in GSH metabolism.