Evoking Ferroptosis by Synergistic Enhancement of a Cyclopentadienyl Iridium-Betulin Immune Agonist.

Angew Chem Int Ed Engl

MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, IGCME, GBRCE for Functional Molecular Engineering, Sun Yat-Sen University, Guangzhou, 510275, P. R. China.

Published: November 2023

Ferroptosis is a form of programmed cell death driven by iron-dependent lipid peroxidation (LPO) with the potential for antitumor immunity activation. In this study, a nonferrous cyclopentadienyl metal-based ferroptosis inducer [Ir(Cp*)(Bet)Cl]Cl (Ir-Bet) was developed by a metal-ligand synergistic enhancement (MLSE) strategy involving the reaction of [Ir(Cp*)Cl] Cl with the natural product Betulin. The fusion of Betulin with iridium cyclopentadienyl (Ir-Cp*) species as Ir-Bet not only tremendously enhanced the antiproliferative activity toward cancer cells, but also activated ferritinophagy for iron homeostasis regulation by PI3K/Akt/mTOR cascade inhibition with a lower dosage of Betulin, and then evoked an immune response by nuclear factor kappa-B (NF-κB) activation of Ir-Cp* species. Further immunogenic cell death (ICD) occurred by remarkable ferroptosis through glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) deactivation and ferritinophagy. An in vivo vaccination experiment demonstrated desirable antitumor and immunogenic effects of Ir-Bet by increasing the ratio of cytotoxic T cells (CTLs)/regulatory T cells (Tregs).

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.202312897DOI Listing

Publication Analysis

Top Keywords

synergistic enhancement
8
cell death
8
ir-cp* species
8
evoking ferroptosis
4
ferroptosis synergistic
4
enhancement cyclopentadienyl
4
cyclopentadienyl iridium-betulin
4
iridium-betulin immune
4
immune agonist
4
agonist ferroptosis
4

Similar Publications

Tomato (Solanum lycopersicum) is an important crop but frequently experiences saline-alkali stress. Our previous studies have shown that exogenous spermidine (Spd) could significantly enhance the saline-alkali resistance of tomato seedlings, in which a high concentration of Spd and jasmonic acid (JA) exerted important roles. However, the mechanism of Spd and JA accumulation remains unclear.

View Article and Find Full Text PDF

Research into the role of probiotics-often referred to as "living supplements"-in cancer therapy is still in its early stages, and uncertainties regarding their effectiveness remain. Relevantly, chemopreventive and therapeutic effects of probiotics have been determined. There is also substantial evidence supporting their potential in cancer treatment such as immunotherapy.

View Article and Find Full Text PDF

 Combination therapy, which synergistically enhances treatment efficacy and inhibits disease progression through the combined effects of multiple drugs, has emerged as a mainstream approach for treating complex diseases and alleviating symptoms. However, drug-drug interactions (DDIs) can sometimes lead to adverse reactions, potentially endangering lives. Therefore, developing efficient and accurate DDI prediction methods is crucial for elucidating drug mechanisms and preventing side effects.

View Article and Find Full Text PDF

The gut microbiome is a complex system that directly interacts with and influences many systems in the body. This delicate balance of microbiota plays an important role in health and disease and is highly influenced by lifestyle factors and the surrounding environment. As further research emerges, understanding the full potential of the gut microbiome and the impact of using nutraceuticals to positively influence its function may open the door to greater therapeutic outcomes in the treatment and prevention of disease.

View Article and Find Full Text PDF

ConspectusThe discovery of reversible hydrogenation using metal-free phosphoborate species in 2006 marked the official advent of frustrated Lewis pair (FLP) chemistry. This breakthrough revolutionized homogeneous catalysis approaches and paved the way for innovative catalytic strategies. The unique reactivity of FLPs is attributed to the Lewis base (LB) and Lewis acid (LA) sites either in spatial separation or in equilibrium, which actively react with molecules.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!