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Published on: September 18, 2013
Evaluating indole‑gold(I) based complexes as potential anti lymphoma agents by disrupting the thioredoxin
Sicong Wang1, Min Shan2, Zhongren Xu2
1School of Environment and Science, Griffith University, Brisbane, Qld 4111, Australia; Institute for Biomedicine and Glycomics, Griffith University, Brisbane, Qld 4111, Australia.
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.
Insights
New indole-gold(I) complexes show potent anti-lymphoma activity by inhibiting antioxidant systems like thioredoxin reductase (TrxR) and glutathione peroxidase (Gpx), potentially inducing ferroptosis.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Antioxidant systems, including thioredoxin (Trx) and glutathione (GSH), are crucial for cancer cell survival and represent therapeutic targets.
- Overexpression of Trx and GSH systems protects cancer cells from reactive oxygen species (ROS), contributing to treatment resistance.
- Metal-based complexes, particularly gold compounds, have shown anticancer effects by targeting thioredoxin reductase (TrxR), but face challenges with selectivity and side effects.
Purpose of the Study:
- To synthesize and evaluate novel indole-metal complexes for antiproliferative activity against lymphoma cell lines.
- To investigate the mechanism of action of promising compounds, focusing on antioxidant system inhibition and ferroptosis induction.
- To assess the in vivo anti-angiogenic potential of the most effective complexes.
Main Methods:
- Synthesis of eleven new indole-metal complexes (gold, iron, cobalt).
- Assessment of antiproliferative activity in lymphoma cell lines.
- Enzyme inhibition assays for TrxR, Gpx, and glutathione reductase (GR).
- Analysis of ferroptosis-related gene expression and lipid peroxidation.
- In vivo anti-angiogenesis assay using zebrafish embryos.
Main Results:
- Indole-gold(I)-based complexes exhibited significant anti-lymphoma activity, superior to indole-iron and cobalt complexes.
- The active gold complexes selectively inhibited TrxR and Gpx, but not GR.
- Two specific complexes (3h and 3i) induced ferroptosis by upregulating related genes and increasing lipid peroxidation.
- In vivo studies demonstrated that complexes 3h and 3i significantly inhibited angiogenesis in zebrafish embryos.
Conclusions:
- Novel indole-gold(I) complexes are effective inhibitors of TrxR and Gpx in lymphoma cells.
- Complexes 3h and 3i show potential as anticancer agents by inducing ferroptosis and inhibiting angiogenesis.
- These findings support further investigation of these compounds as novel therapeutic strategies for lymphoma.
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