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Anticancer Cyclometalated Iridium(III) Complexes with Planar Ligands: Mitochondrial DNA Damage and Metabolism
Jian-Jun Cao1, Yue Zheng1, Xiao-Wen Wu1
1MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry , Sun Yat-Sen University , Guangzhou 510275 , China.
Abstract:
Emerging studies have shown that mitochondrial DNA (mtDNA) is a potential target for cancer therapy. Herein, six cyclometalated Ir(III) complexes Ir1-Ir6 containing a series of extended planar diimine ligands have been designed and assessed for their efficacy as anticancer agents. Ir1-Ir6 show much higher cytotoxicity than cisplatin and they can effectively localize to mitochondria. Among them, complexes Ir3 and Ir4 with dipyrido[3,2- a:2',3'- c]phenazine (dppz) ligands can bind to DNA tightly in vitro, intercalate to mtDNA in situ, and induce mtDNA damage. Ir3- and Ir4-impaired mitochondria exhibit decline of mitochondrial membrane potential, disability of adenosine triphosphate generation, disruption of mitochondrial energetic and metabolic status, which subsequently cause protective mitophagy, G0/G1 phase cell cycle arrest, and apoptosis. In vivo antitumor evaluations also show that Ir4 can inhibit tumor xenograft growth effectively. Overall, our work proves that targeting the mitochondrial genome may present an effective strategy to develop metal-based anticancer agents to overcome cisplatin resistance.
Insights
New iridium complexes target mitochondrial DNA (mtDNA) for cancer therapy, showing higher efficacy than cisplatin. These compounds induce mitochondrial damage, leading to apoptosis and inhibiting tumor growth, offering a novel strategy against drug resistance.
Area of Science:
- Inorganic Chemistry
- Cancer Biology
- Mitochondrial Medicine
Background:
- Mitochondrial DNA (mtDNA) is an emerging target for novel cancer therapies.
- Developing metal-based anticancer agents to overcome cisplatin resistance is a critical challenge.
Purpose of the Study:
- To design and evaluate cyclometalated iridium(III) complexes as potential anticancer agents targeting mtDNA.
- To investigate the mechanism of action of these complexes in cancer cells and in vivo.
Main Methods:
- Synthesis and characterization of six cyclometalated iridium(III) complexes (Ir1-Ir6) with extended planar diimine ligands.
- In vitro cytotoxicity assays, cellular uptake studies, and mitochondrial localization assessments.
- DNA binding assays, mtDNA intercalation and damage studies, and analysis of mitochondrial function (membrane potential, ATP generation).
- Cell cycle analysis, apoptosis assays, and in vivo antitumor efficacy evaluation in tumor xenograft models.
Main Results:
- Complexes Ir1-Ir6 exhibited significantly higher cytotoxicity than cisplatin and localized effectively to mitochondria.
- Complexes Ir3 and Ir4, featuring dipyrido[3,2- a:2',3'- c]phenazine (dppz) ligands, tightly bound to DNA, intercalated into mtDNA, and induced mtDNA damage.
- Mitochondrial impairment in Ir3- and Ir4-treated cells included reduced membrane potential, decreased ATP generation, and disrupted energy metabolism.
- These mitochondrial dysfunctions triggered mitophagy, G0/G1 cell cycle arrest, and apoptosis.
- Complex Ir4 demonstrated effective inhibition of tumor xenograft growth in vivo.
Conclusions:
- Targeting the mitochondrial genome is a promising strategy for developing metal-based anticancer agents.
- The designed iridium(III) complexes, particularly Ir3 and Ir4, show potential for overcoming cisplatin resistance.
- These findings provide a foundation for developing novel metallodrugs that exploit mitochondrial pathways for cancer treatment.
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