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Anticancer behaviour of simplified lysosome-targeted half-sandwich iridium(III) xanthate complexes towards A549 cell
Benlian Xue1, Youkun Zang1, Wang Lv1
1Key Laboratory of Life-Organic Analysis of Shandong Province, Institute of Anticancer Agents Development and Theranostic Application, School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China.
Abstract:
Although widely used clinically, the extensive nephrotoxicity and drug resistance of platinum-based metallic anticancer drugs have spurred the research and development of non‑platinum-based metallic anticancer drugs. Half-sandwich iridium(III) (IrIII) complexes have become a research hotspot in this field due to their excellent anticancer activity, structural tunability, and unique mechanism of action different from that of cisplatin. Then two half-sandwich IrIII xanthate complexes with a simple structure were prepared in this study. In vitro anti-proliferative evaluation showed that these two complexes enjoyed favorable activity towards A549 lung cancer cells in comparison to cisplatin, and could also effectively inhibit cell migration. Further research showed that Ir1 could target lysosomes (PCC: 0.85) and lead to lysosomal damage, then disturbing the cell cycle arrest (G0/G1 phase), decreasing mitochondrial membrane potential and inducing the improvement of intracellular reactive oxygen species levels. Western blotting also confirmed the existence of a lysosomal-mitochondrial apoptotic anticancer pathway. Collectively, these structurally simple yet highly active IrIII complexes provide a valuable foundation for the rational design and development of novel non‑platinum-based metallic anticancer drugs.
Insights
New iridium(III) complexes show potent anticancer activity against lung cancer cells, offering a promising alternative to platinum-based drugs. These compounds target lysosomes and mitochondria, inducing cancer cell death through a novel apoptotic pathway.
Area of Science:
- Inorganic Chemistry
- Medicinal Chemistry
- Cancer Biology
Background:
- Platinum-based anticancer drugs face challenges like nephrotoxicity and drug resistance.
- Half-sandwich iridium(III) complexes are emerging as promising alternatives due to their unique mechanisms and tunable structures.
Purpose of the Study:
- To synthesize and evaluate novel half-sandwich iridium(III) xanthate complexes for anticancer properties.
- To investigate the mechanism of action of these iridium complexes in lung cancer cells.
Main Methods:
- Synthesis of two half-sandwich iridium(III) xanthate complexes.
- In vitro anti-proliferative assays against A549 lung cancer cells.
- Cell migration inhibition assays.
- Confocal microscopy for lysosomal targeting and damage assessment.
- Flow cytometry for mitochondrial membrane potential and reactive oxygen species analysis.
- Western blotting to confirm apoptotic pathways.
Main Results:
- The synthesized iridium(III) complexes exhibited significant anti-proliferative activity against A549 lung cancer cells, outperforming cisplatin.
- The complexes effectively inhibited cancer cell migration.
- One complex (Ir1) was found to target lysosomes, causing damage and subsequently inducing G0/G1 cell cycle arrest.
- Ir1 treatment led to decreased mitochondrial membrane potential and increased intracellular reactive oxygen species.
- Western blotting confirmed the activation of a lysosomal-mitochondrial apoptotic pathway.
Conclusions:
- Structurally simple iridium(III) xanthate complexes demonstrate potent anticancer activity and a novel mechanism of action.
- These complexes offer a promising foundation for developing next-generation non-platinum-based anticancer drugs.
- Targeting the lysosomal-mitochondrial pathway presents a viable strategy for cancer therapy.
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