Evaluating indole‑gold(I) based complexes as potential anti lymphoma agents by disrupting the thioredoxin reductase/glutathione peroxidase axis

Abstract

Antioxidant systems, especially the thioredoxin (Trx) and glutathione (GSH) systems, represent promising targets for cancer therapy. Overexpression of these systems has been reported in many cancers, including lymphoma and considered as a mechanism of protection for cancer cells from the high levels of reactive oxygen species (ROS). Over several decades, metal-based complexes including gold complexes such as auranofin have shown anticancer activity by targeting thiols and selenol groups in the active site of thioredoxin reductase (TrxR). However, lack of selectivity, severe side effects or resistance to therapy have been widely reported. Recently, glutathione peroxidase (Gpx) has been reported as one of the key proteins that regulate ferroptosis in cells. To expand the armory for targeting antioxidant systems, in this study eleven new indole-metal complexes were synthesized and assessed for their antiproliferative activity in lymphoma cell lines. The indole‑gold(I)-based complexes showed the best anti-lymphoma activity via inhibiting TrxR and Gpx, but not glutathione reductase (GR), when compared to the indole‑iron-based and cobalt-based complexes. Further investigation revealed that two of the indole‑gold(I)-based complexes, 3h and 3i, induced the expression of ferroptosis-related genes and an increase in lipid peroxidation, indicating activation of ferroptosis in these cells. The in vivo study also revealed that these complexes significantly inhibited angiogenesis by reducing formation of blood vessels in zebra fish embryos. Overall, these results show the potential of 3h and 3i as TrxR and Gpx inhibitors in lymphoma cells, warranting further assessment as anticancer agents and potential inducers of ferroptosis.