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Dinuclear orthometallated gold(I)-gold(III) anticancer complexes with potent in vivo activity through an ROS-dependent mechanism
- Source :
- Metallomics. 13
- Publication Year :
- 2021
- Publisher :
- Oxford University Press (OUP), 2021.
-
Abstract
- Increasingly explored over the last decade, gold complexes have shown great promise in the field of cancer therapeutics. A major obstacle to their clinical progression has been their lack of in vivo stability, particularly for gold(III) complexes, which often undergo a facile reduction in the presence of biomolecules such as glutathione. Herein, we report a new class of promising anticancer gold(I)–gold(III) complexes with the general formula [XAuI(μ-2-C6F4PPh2)(κ2-2-C6F4PPh2)AuIIIX] [X = Cl (1), Br (2), NO3 (3)] which feature two gold atoms in different oxidation states (I and III) in a single molecule. Interestingly, gold(I)–gold(III) complexes (1–3) are stable against glutathione reduction under physiological-like conditions. In addition, complexes 1–3 exhibit significant cytotoxicity (276-fold greater than cisplatin) toward the tested cancer cells compared to the noncancerous cells. Moreover, the gold(I)–gold(III) complexes do not interact with DNA-like cisplatin but target cellular thioredoxin reductase, an enzyme linked to the development of cisplatin drug resistance. Complexes 1–3 also showed potential to inhibit cancer and endothelial cell migration, as well as tube formation during angiogenesis. In vivo studies in a murine HeLa xenograft model further showed the gold compounds may inhibit tumor growth on par clinically used cisplatin, supporting the significant potential this new compound class has for further development as cancer therapeutic.
- Subjects :
- Thioredoxin reductase
Biophysics
Mice, Nude
Uterine Cervical Neoplasms
Antineoplastic Agents
Apoptosis
010402 general chemistry
01 natural sciences
Biochemistry
Biomaterials
HeLa
Mice
Gold Compounds
Coordination Complexes
In vivo
Tumor Cells, Cultured
medicine
Animals
Humans
Cytotoxicity
Cell Proliferation
Tube formation
Cisplatin
Mice, Inbred BALB C
biology
010405 organic chemistry
Chemistry
Cell Cycle
Metals and Alloys
biology.organism_classification
Xenograft Model Antitumor Assays
Combinatorial chemistry
0104 chemical sciences
Chemistry (miscellaneous)
Cancer cell
Female
Gold
Reactive Oxygen Species
medicine.drug
Subjects
Details
- ISSN :
- 1756591X
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Metallomics
- Accession number :
- edsair.doi.dedup.....1d03bbc03e0019889b7dd2e8f9479261