What question did this study set out to answer?

The aim is to explore the mechanism of half-sandwich iridium(III) compounds in overcoming cancer resistance.

June 18, 2026Open Access

Mechanistic Exploration of Half-Sandwich Iridium(III) Anticancer Compounds through Integrated Cellular, Proteomic, and In Vivo Analyses

PŠPavel ŠtarhaPalacký University Olomouc JFJaroslava FriedeckáCzech Academy of Sciences, Institute of Experimental Botany RHRenata HéžováVeterinary Research Institute

Key Points

The aim is to explore the mechanism of half-sandwich iridium(III) compounds in overcoming cancer resistance.
Tested iridium(III) compounds in 2D and 3D cancer cell cultures, particularly in cisplatin-resistant lung carcinoma.
Conducted multiomics profiling to investigate cellular stress responses and biochemical changes.
Performed in vivo analysis to assess tumor growth suppression and toxicity.
Compound 3 specifically outperformed cisplatin in inhibiting MOR/CPR cell growth (exact metrics not provided).
Showed non-DNA-targeted mechanism involving rapid stress responses, leading to translational shutdown and metabolic shifts.
In vivo results indicate tumor growth suppression and low systemic toxicity with activated apoptosis.

Abstract

High Resolution Image Download MS PowerPoint Slide New half-sandwich iridium(III) compounds Ir(η 5 -Cp x )Cl(L1–3)PF 6 ( 1 – 6 ), combining Cp* or Cp ph with N,P-coordinated phosphinoalkylamines L1–L3, were tested in different cancer cells (2D and 3D cultures), including MOR/CPR cisplatin-resistant lung carcinoma. Best-performing compound 3 outperformed its Cp ph analogue 6 and cisplatin in MOR/CPR cells while sparing noncancerous cells. Multiomics profiling shows a non-DNA-targeted mechanism: rapid integrated stress response with ER stress (DDIT3/CHOP) and oxidative stress (HMOX1, ATF3), nucleolar stress, and primary inhibition of ribosome biogenesis and mitochondrial translation. These changes drive translational shutdown, suppression of oxidative phosphorylation with a glycolytic shift, and G 1 arrest, alongside endolysosomal remodeling (enhanced vesicular uptake, reduced degradative capacity) that favors intracellular retention. The phenotype is predominantly cytostatic with apoptotic priming. In vivo, 3 suppressed tumor growth and activated apoptosis with low systemic toxicity. Compound 3 thus emerges as a promising prototype Ir(III) metallodrug that disrupts nucleolar, mitochondrial, and lysosomal homeostasis to overcome resistance.

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