Sulfur-Coordinated Organoiridium(III) Complexes Exert Breast Anticancer Activity via Inhibition of Wnt/β-Catenin Signaling.

Abstract

The sulfur-coordinated organoiridium(III) complexes pbtIrSS and ppyIrSS, which contain C,N and S,S (dithione) chelating ligands, were found to inhibit breast cancer tumorigenesis and metastasis by targeting Wnt/β-catenin signaling for the first time. Treatment with pbtIrSS and ppyIrSS induces the degradation of LRP6, thereby decreasing the protein levels of DVL2, β-catenin and activated β-catenin, resulting in downregulation of Wnt target genes CD44 and survivin. Additionally, pbtIrSS and ppyIrSS can suppress cell migration and invasion of breast cancer cells. Furthermore, both complexes show the ability to inhibit sphere formation and mediate the stemness properties of breast cancer cells. Importantly, pbtIrSS exerts potent anti-tumor and anti-metastasis effects in mouse xenograft models through the blockage of Wnt/β-catenin signaling. Taken together, our results indicate that pbtIrSS has great potential to be developed as a breast cancer therapeutic agent with a novel mechanism.

• Authors: Qi Sun, Yi Wang, Qiuxia Fu, Ai Ouyang, Shanshan Liu, Zhongyuan Wang, Zijie Su, Jiaxing Song, Qianling Zhang, Pingyu Zhang, Desheng Lu
• Journal: Angewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 60 Issue 9 Pg. 4841-4848 (02 23 2021) ISSN: 1521-3773 [Electronic] Germany
• PMID: 33244858 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Wiley-VCH GmbH.

Chemical References

• Antineoplastic Agents
• Coordination Complexes
• LRP6 protein, human
• Low Density Lipoprotein Receptor-Related Protein-6
• Organometallic Compounds
• beta Catenin
• Iridium
• Sulfur
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Cisplatin (therapeutic use)
• Coordination Complexes (chemistry, pharmacology, therapeutic use)
• Female
• Humans
• Iridium (chemistry)
• Low Density Lipoprotein Receptor-Related Protein-6 (genetics, metabolism)
• Lung Neoplasms (drug therapy, secondary)
• Mice
• Mice, Nude
• Organometallic Compounds (chemistry)
• Sulfur (chemistry)
• Transplantation, Heterologous
• Wnt Signaling Pathway (drug effects)
• beta Catenin (metabolism)