Abstract
BackgroundPlatinum-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.MethodsKinase 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.ResultsWe 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.ConclusionsOur 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.
Highlights
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
Rhenium N-heterocyclic carbene (Re-NHC) complexes with inhibitory activity towards FGFR1 and Src We recently showed that Re-NHC complexes suppress the growth of pancreatic cancer cell lines by blocking the cells in the G2/M phase via a mechanism involving the inhibition of phosphorylation of aurora kinase A
Compounds JVG045 and ps27 showed > 50% inhibitory activity towards Fibroblast Growth Factor Receptor (FGFR1) and Src (Fig. 1a) and did not inhibit any of the other kinases tested. Further evidence for this inhibition was obtained by Western blot analyses (Fig. 1b), which were used to compare the levels of phosphorylated Fibroblast Growth Factor Receptor in two different pancreatic cancer cell lines (HPAF-II and AsPC-1) using glyceraldehyde-3phosphate dehydrogenase (GAPDH) to normalise protein content
Summary
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. They are not universally effective, and patients often suffer severe side effects because of their lack of cellular selectivity. The development of chemoresistance is a significant limiting factor in the use of this drug [2, 4] Carboplatin, another platinum-based drug that directly interferes with DNA metabolism, leads to the formation of cross-links in a manner similar to cisplatin. Because of the severe side effects that result from the use of all platinum-based drugs, other metal compounds are being studied for their anti-proliferative activity, with the goal of discovering new agents that are better tolerated by cancer patients
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