Targeting Glutathione Metabolism: Partner in Crime in Anticancer Therapy

Abstract

Glutathione (GSH) is the predominant low-molecular-weight antioxidant with a ubiquitous distribution inside the cell. The steady-state level of cellular GSH is dependent on the balance between synthesis, hydrolysis, recycling of glutathione disulphide (GSSG) as well as cellular extrusion of reduced, oxidized, or conjugated-forms. The augmented oxidative stress typical of cancer cells is accompanied by an increase of glutathione levels that confers them growth advantage and resistance to a number of chemotherapeutic agents. Targeting glutathione metabolism has been widely investigated for cancer treatment although GSH depletion as single therapeutic strategy has resulted largely ineffective if compared with combinatorial approaches. In this review, we circumstantiate the role of glutathione in tumour development and progression focusing on how interfering with different steps of glutathione metabolism can be exploited for therapeutic purposes. A dedicated section on synthetic lethal interactions with GSH modulators will highlight the promising option of harnessing glutathione metabolism for patient-directed therapy in cancer.

Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis

“…As the most abundant antioxidant molecule in live cells, GSH is frequently upregulated in cancer cells and essential for the fast proliferation of cancer cells. 4,34,61 Thus, targeting GSH inhibition has been considered as an effective way to kill cancer cells. 8,62 The release of the active drug Gem and conversion of the antioxidant GSH to ROS account for the enhanced cytotoxicity of Se-Gem.…”

Cancer-Selective Treatment of Cancerous and Non-Cancerous Human Cervical Cell Models by a Non-Thermally Operated Electrosurgical Argon Plasma Device

“…As a potential target in anti-cancer therapy, intracellular GSH levels have been investigated intensively in different fields of oncology and were shown to allow cancer cells to cope with the oxidative stress caused by their increased metabolism and proliferation rate. In many cancer cells, strongly increased GSH levels are observed compared to non-cancerous cells [22]. The capability of NAC to counteract CAP-mediated apoptosis has been demonstrated on prostate cancer cells and other tumor entities [2,11,13].…”

Dendropanax morbifera Leaf Extracts Improved Alcohol Liver Injury in Association with Changes in the Gut Microbiota of Rats

“…The effects of GST and GR related to the metabolism of GSH on the enzymatic activity were confirmed. GSH, which acts as an antioxidant in the body, reacts with radicals via GST to form inactive glutathione disulfide (GSSG), with the cycle then closing via conversion of GSSG back into active GSH by GR [ 42 ]. Both GST and GR activities were significantly decreased in the Ethanol group compared to the control group, but the intake of DML extract led to the recovery of their activities up to that of the control group.…”