Rhenium N-heterocyclic carbene complexes block growth of aggressive cancers by inhibiting FGFR- and SRC-mediated signalling

Background Platinum-based anticancer drugs have been at the frontline of cancer therapy for the last 40 years, and are used in more than half of all treatments for different cancer types. However, they are not universally effective, and patients often suffer severe side effects because of their lack...

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Published in:Journal of experimental & clinical cancer research 2020-12, Vol.39 (1), p.1-17, Article 276
Main Authors: Domenichini, Alice, Casari, Ilaria, Simpson, Peter V, Desai, Nima Maheshkumar, Chen, Lingfeng, Dustin, Christopher, Edmands, Jeanne S, van der Vliet, Albert, Mohammadi, Moosa, Massi, Massimiliano, Falasca, Marco
Format: Article
Language:English
Subjects:
Cancer
Carboplatin
Care and treatment
Chromatography
FGFR
Glycerol
Health aspects
Heterocyclic compounds
Kinases
Ligands
Neuroblastoma
Pancreatic cancer
Phosphatase
Phosphorylation
Prostate cancer
Proteins
Rhenium complexes
Src
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Summary:Background Platinum-based anticancer drugs have been at the frontline of cancer therapy for the last 40 years, and are used in more than half of all treatments for different cancer types. However, they are not universally effective, and patients often suffer severe side effects because of their lack of cellular selectivity. There is therefore a compelling need to investigate the anticancer activity of alternative metal complexes. Here we describe the potential anticancer activity of rhenium-based complexes with preclinical efficacy in different types of solid malignancies. Methods Kinase profile assay of rhenium complexes. Toxicology studies using zebrafish. Analysis of the growth of pancreatic cancer cell line-derived xenografts generated in zebrafish and in mice upon exposure to rhenium compounds. Results We describe rhenium complexes which block cancer proliferation in vitro by inhibiting the signalling cascade induced by FGFR and Src. Initially, we tested the toxicity of rhenium complexes in vivo using a zebrafish model and identified one compound that displays anticancer activity with low toxicity even in the high micromolar range. Notably, the rhenium complex has anticancer activity in very aggressive cancers such as pancreatic ductal adenocarcinoma and neuroblastoma. We demonstrate the potential efficacy of this complex via a significant reduction in cancer growth in mouse xenografts. Conclusions Our findings provide a basis for the development of rhenium-based chemotherapy agents with enhanced selectivity and limited side effects compared to standard platinum-based drugs. Keywords: Rhenium complexes, Pancreatic cancer, Neuroblastoma, FGFR, Src
ISSN:1756-9966
0392-9078
1756-9966
DOI:10.1186/s13046-020-01777-7