Targeting Glutathione metabolism in cancer - a new therapeutic approach

Abstract

Antioxidants have long been considered as potential cancer-preventive agents, though most clinical trials have failed to demonstrate significant benefits from antioxidant supplements. Recent scientific findings, however, have shifted this view by suggesting that pro-oxidant therapies could offer promising anti-cancer strategies. Despite this potential, few pro-oxidant therapies have successfully transitioned into clinical use. Herein, we aimed to determine the impact of antioxidant-targeting therapies on cancer progression, with a focus on pro-oxidative drugs as novel treatments. To explore how antioxidant supplementation affects the initiation and progression of colorectal cancer, we treated a mouse model of hereditary colorectal cancer (ApcMin/+) with N-acetyl cysteine (NAC) and Vitamin E. Our results showed that antioxidant supplementation with NAC, at serum concentrations equivalent to patients given prescription NAC, promoted tumor progression and worsened histological tumor grading. We then examined how nutritional factors affect susceptibility to the glutathione-depleting drug buthionine sulfoximine (BSO) and discovered that amino acid availability is a key factor governing ferroptosis sensitivity, an iron-dependent form of cell death triggered by lipid peroxidation. This sensitization was mediated by the integrated stress response (ISR) pathway, with the transcription factor ATF4 lowering the threshold for lipid peroxidation. To identify novel targets for pro-oxidant therapy, we performed a CRISPR-Cas9 screen to uncover genes that exacerbated the effects of three different pro-oxidant drugs. Notably, we found that activation of the Wnt signaling pathway increased iron uptake via the transferrin receptor, enhancing the effects of BSO treatment. In our final study, we focused on identifying targets of the transcription factor ATF4. We discovered that TRIB3 may represent a novel therapeutic target in combination with BSO treatment. In conclusion, our findings raise concerns about the use of antioxidant supplements in individuals at risk of developing colorectal cancer. Amino acid restriction presents a promising avenue for further investigation as a therapeutic intervention alongside ferroptosis-inducing drugs. Additionally, Wnt-targeting agents such as CHIR show potential as effective combination therapies with BSO.