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

Journal of Experimental & Clinical Cancer Research

Jeanne S. Edmands¹  Peter V. Simpson²  Massimiliano Massi²  Moosa Mohammadi³  Lingfeng Chen³  Christopher Dustin⁴  Albert van der Vliet⁴  Ilaria Casari⁵  Alice Domenichini⁵  Nima Maheshkumar Desai⁵  Marco Falasca⁵ 

[1] Curtin Health Innovation Research Institute, Curtin University;Curtin Institute of Functional Molecules and Interfaces, Department of Chemistry, Curtin University;Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine;Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont;Metabolic Signalling Group, School of Pharmacy & Biomedical Sciences, Curtin University;

关键词: Rhenium complexes;    Pancreatic cancer;    Neuroblastoma;    FGFR;    Src;   

DOI  :  10.1186/s13046-020-01777-7

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown