PUBLICATION
Rhenium N-heterocyclic carbene complexes block growth of aggressive cancers by inhibiting FGFR- and SRC-mediated signalling
- Authors
- Domenichini, A., Casari, I., Simpson, P.V., Desai, N.M., Chen, L., Dustin, C., Edmands, J.S., van der Vliet, A., Mohammadi, M., Massi, M., Falasca, M.
- ID
- ZDB-PUB-201209-3
- Date
- 2020
- Source
- Journal of experimental & clinical cancer research : CR 39: 276 (Journal)
- Registered Authors
- Keywords
- FGFR, Neuroblastoma, Pancreatic cancer, Rhenium complexes, Src
- MeSH Terms
-
- Animals
- Cell Line, Tumor
- Coordination Complexes/chemistry
- Coordination Complexes/pharmacology*
- Humans
- Methane/analogs & derivatives*
- Methane/chemistry
- Methane/metabolism
- Methane/therapeutic use
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Reactive Oxygen Species
- Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors*
- Receptor, Fibroblast Growth Factor, Type 1/metabolism*
- Rhenium/pharmacology*
- Signal Transduction/drug effects
- Xenograft Model Antitumor Assays
- Zebrafish
- src-Family Kinases/antagonists & inhibitors*
- src-Family Kinases/metabolism
- PubMed
- 33287862 Full text @ J. Exp. Clin. Cancer Res.
Citation
Domenichini, A., Casari, I., Simpson, P.V., Desai, N.M., Chen, L., Dustin, C., Edmands, J.S., van der Vliet, A., Mohammadi, M., Massi, M., Falasca, M. (2020) Rhenium N-heterocyclic carbene complexes block growth of aggressive cancers by inhibiting FGFR- and SRC-mediated signalling. Journal of experimental & clinical cancer research : CR. 39:276.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping