PUBLICATION
Peroxiredoxin Depletion and Oxidative Stress by Cyclometalated Ir(III)-Isatin Complexes Renders Ferroptosis and Autophagic Cell Death in Triple-Negative Breast Cancer
- Authors
- Mukherjee, S., Ghosh, S., M, R.D., Roy, S., Roy, S.S., Acharya, M., Kumar, B.K., Mukherjee, A.
- ID
- ZDB-PUB-250729-38
- Date
- 2025
- Source
- Journal of medicinal chemistry : (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Agents*/chemical synthesis
- Antineoplastic Agents*/chemistry
- Antineoplastic Agents*/pharmacology
- Autophagy*/drug effects
- Cell Line, Tumor
- Coordination Complexes*/chemical synthesis
- Coordination Complexes*/chemistry
- Coordination Complexes*/pharmacology
- Female
- Ferroptosis*/drug effects
- Humans
- Iridium*/chemistry
- Iridium*/pharmacology
- Oxidative Stress*/drug effects
- Peroxiredoxins*/metabolism
- Reactive Oxygen Species/metabolism
- Triple Negative Breast Neoplasms*/drug therapy
- Triple Negative Breast Neoplasms*/metabolism
- Triple Negative Breast Neoplasms*/pathology
- Zebrafish
- PubMed
- 40726255 Full text @ J. Med. Chem.
Citation
Mukherjee, S., Ghosh, S., M, R.D., Roy, S., Roy, S.S., Acharya, M., Kumar, B.K., Mukherjee, A. (2025) Peroxiredoxin Depletion and Oxidative Stress by Cyclometalated Ir(III)-Isatin Complexes Renders Ferroptosis and Autophagic Cell Death in Triple-Negative Breast Cancer. Journal of medicinal chemistry. :.
Abstract
The ability to induce nonapoptotic cell death is critical to fight apoptosis-resistant cancers. Excessive reactive oxygen species (ROS) can promote nonapoptotic cell death. We report six potent cyclometalated iridium(III) complexes derived from isatin-hydrazone Schiff bases with nanomolar IC50 values against pancreatic (MIA-PaCa-2, PANC-1) and breast (MDA-MB-231, MCF-7) cancer cells. These metal-based anticancer agents promote excess ROS accumulation, triggering ferroptosis and autophagy. The lead Ir(III) complex (1), bearing an imidazole-isatin ligand, shows high aqueous stability, maximum cellular uptake, and the strongest cytotoxicity. Proteomic analysis reveals upregulation of S100-A8, RAB27A, and Galectin-1 as an adaptive mechanism to regulate ROS. However, excessive ROS production surpasses the capacity of cellular antioxidant defenses, downregulating ROS-controlling proteins such as peroxiredoxins (Prx) and superoxide dismutase (SOD) accompanied by overexpression of heme oxygenase contributing to lipid peroxidation. Additionally, the complexes reduce inflammation by suppressing MIF and TGF-β signaling. Low systemic toxicity and antiangiogenic activity in zebrafish further support their therapeutic potential.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping