The unfolded protein response-glutathione metabolism axis: A novel target of a cycloruthenated complexes bypassing tumor resistance mechanisms

• Published in: Cancer letters 2024-03, Vol.585, p.216671-216671, Article 216671
• Main Authors: Riegel, Gilles, Orvain, Christophe, Recberlik, Sevda, Spaety, Marie-Elodie, Poschet, Gernot, Venkatasamy, Aina, Yamamoto, Masami, Nomura, Sachiyo, Tsukamoto, Tetsyua, Masson, Murielle, Gross, Isabelle, Le Lagadec, Ronan, Mellitzer, Georg, Gaiddon, Christian
• Format: Article
• Language: English
• Subjects: Caspase-independent apoptosis; ER stress; Glutathione; Life Sciences; Metabolism; RDC11; Transsulfuration; UPR
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2024.216671

Platinum-based drugs remain the reference treatment for gastric cancer (GC). However, the frequency of resistance, due to mutations in TP53 or alterations in the energy and redox metabolisms, impairs the efficacy of current treatments, highlighting the need for alternative therapeutic options. Here, we show that a cycloruthenated compound targeting the redox metabolism, RDC11, induces higher cytotoxicity than oxaliplatin in GC cells and is more potent in reducing tumor growth in vivo. Detailed investigations into the mode of action of RDC11 indicated that it targets the glutathione (GSH) metabolism, which is an important drug resistance mechanism. We demonstrate that cycloruthenated complexes regulate the expression of enzymes of the transsulfuration pathway via the Unfolded Protein Response (UPR) and its effector ATF4. Furthermore, RDC11 induces the expression of SLC7A11 encoding for the cystine/glutamate antiporter xCT. These effects lead to a lower cellular GSH content and elevated oxygen reactive species production, causing the activation of a caspase-independent apoptosis. Altogether, this study provides the first evidence that cycloruthenated complexes target the GSH metabolism, neutralizing thereby a major resistance mechanism towards platinum-based chemotherapies and anticancer immune response. •A Cycloruthenated compound induces higher cytotoxicity than oxaliplatin in gastric cancer cells and strongly reduces tumor growth in vivo.•Anti-cancer cycloruthenated compounds target the redox metabolism in gastric cancer cells.•Cycloruthenated compounds target the glutathione (GSH) metabolism through the Unfolded Protein Response (UPR), and its effector ATF4.•These effects lead to a lower cellular GSH content and higher oxygen reactive species production, leading to caspase-independent apoptosis.