Colorectal cancer (CRC) remains a major global health challenge, in which chronic inflammation and redox dysregulation are key drivers of tumor progression. Here, we report a rationally designed famil Show more
Colorectal cancer (CRC) remains a major global health challenge, in which chronic inflammation and redox dysregulation are key drivers of tumor progression. Here, we report a rationally designed family of NSAID-derived alkyne ligands coordinated to JohnPhos-gold(I) fragments, affording eight new alkynyl gold(I) derivatives. Complexes based on naproxen, ibuprofen, and salicylic acid derivatives display potent antiproliferative activity against Caco-2/TC7 colon cancer cells, outperforming oxaliplatin and being comparable to auranofin, while showing markedly reduced cytotoxicity in breast cancer lines and nonmalignant cells, thus indicating promising selectivity. Mechanistic studies revealed that the most active complex, [Au(L1)JP] (1), which contains a naproxen-derived alkyne, inhibits thioredoxin reductase (TrxR), triggers ROS overproduction, disrupts mitochondrial membrane potential, and induces G1-phase arrest while only marginally increasing apoptosis. This suggests the involvement of additional forms of cell death or cytostatic effects. Additionally, complex 1 selectively inhibits the enzyme cyclooxygenase-2 (COX-2) over COX-1 and reduces IL-8 expression without affecting PTGS2 transcription, highlighting a post-transcriptional anti-inflammatory action. These results support NSAID-derived alkynyl gold(I) complexes as promising multitarget agents for colorectal cancer intervention, combining disruption and COX-2 modulation. Show less
The Nature Index tracks the affiliations of high-quality scientific articles. Updated monthly, the Nature Index presents research outputs by institution and country. Use the Nature Index to interrogat Show more
The Nature Index tracks the affiliations of high-quality scientific articles. Updated monthly, the Nature Index presents research outputs by institution and country. Use the Nature Index to interrogate publication patterns and to benchmark research performance.
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Targeting inflammation and the molecules involved in the inflammatory process could be an effective cancer prevention and therapy strategy. Therefore, the use of anti-inflammatory strategies, such as Show more
Targeting inflammation and the molecules involved in the inflammatory process could be an effective cancer prevention and therapy strategy. Therefore, the use of anti-inflammatory strategies, such as NSAIDs and metal-based drugs, has become a promising approach for preventing and treating cancer by targeting multiple pathways involved in tumor progression. The present work describes new phosphane gold(I) complexes derived from nonsteroidal anti-inflammatory drugs as multitarget drugs against colon cancer. The antiproliferative effect of the most active complexes, [Au(L3)(JohnPhos)] (3b), [Au(L4)(CyJohnPhos)] (4a) and [Au(L4)(JohnPhos)] (4b) against colon cancer cells (Caco2-/TC7) seems to be mediated by the inhibition of the enzyme cyclooxygenase-1/2, modulation of reactive oxygen species levels by targeting thioredoxin reductase (TrxR) activity, and induction of apoptosis in cancer cells. Additionally, the three complexes exhibit high selectivity index values toward noncancerous cells. The research highlights the importance of maintaining cellular redox balance and the role of TrxR in cancer cell survival. Show less
Mononuclear gold(I) acyclic diaminocarbenes (ADCs) were prepared by the reaction of 1,2-cyclohexanediamine with the corresponding isocyanide complexes [AuCl(CNR)] (R = Cy, t Bu). The Show more
Mononuclear gold(I) acyclic diaminocarbenes (ADCs) were prepared by the reaction of 1,2-cyclohexanediamine with the corresponding isocyanide complexes [AuCl(CNR)] (R = Cy, t Bu). The three-component coupling of aldehydes, amines, and alkynes was investigated by using these gold(I) ADC complexes. The new gold(I) metal complexes are highly efficient catalysts for the synthesis of propargylamines and indolizines in the absence of solvent and in mild conditions. This method affords the corresponding final products with excellent yields in short reaction times. Additionally, chiral gold(I) complexes with ADCs have been prepared and tried in the enantioselective synthesis of propargylamines. Show less
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology Show more
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δ p or its potential component, Δ Ψ , which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1–5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δ p dissipation decreases superoxide formation dependent on Δ p . UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. Critical Issues: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg 2+ , or increased pyruvate accumulation may initiate UCP-mediated redox signaling. Future Directions: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667–714. Show less