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Strategic design and development of a siderophore mimic: pioneering anticancer therapy via ROS generation and ferroptosis.
- Source :
-
Dalton Transactions: An International Journal of Inorganic Chemistry . 8/7/2024, Vol. 53 Issue 29, p12119-12127. 9p. - Publication Year :
- 2024
-
Abstract
- We designed a tris-catecholate-based siderophore mimic, H6-T-CATL, to selectively chelate iron(III) from mitochondrial cytochromes and other iron-containing proteins within cellular matrices. This strategic sequestration aims to trigger apoptosis or ferroptosis in cancer cells through the glutathione (GSH)-dependent release of reduced iron and subsequent ROS-mediated cytotoxicity. Synthesis of H6-T-CATL involved precise peptide coupling reactions. Using the Fe(III)-porphyrin model (Fe-TPP-Cl), akin to cytochrome c, we studied H6-T-CATL's ability to extract iron(III), yielding a binding constant (Krel) of 1014 for the resulting iron(III) complex (FeIII-T-CATL)3−. This complex readily underwent GSH-mediated reduction to release bioavailable iron(II), which catalyzed Fenton-like reactions generating hydroxyl radicals (˙OH), confirmed by spectroscopic analyses. Our research underscores the potential of H6-T-CATL to induce cancer cell death by depleting iron(III) from cellular metalloproteins, releasing pro-apoptotic iron(II). Evaluation across various cancer types, including normal cells, demonstrated H6-T-CATL's cytotoxicity through ROS production, mitochondrial dysfunction, and activation of ferroptosis and DNA damage pathways. These findings propose a novel mechanism for cancer therapy, leveraging endogenous iron stores within cells. H6-T-CATL emerges as a promising next-generation anticancer agent, exploiting iron metabolism vulnerabilities to induce selective cancer cell death through ferroptosis induction. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 14779226
- Volume :
- 53
- Issue :
- 29
- Database :
- Academic Search Index
- Journal :
- Dalton Transactions: An International Journal of Inorganic Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 178562990
- Full Text :
- https://doi.org/10.1039/d4dt01461h