Novel iron chelator SK4 induces cancer cell death and enhances the efficacy of the PARP inhibitor Rucaparib


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Gina Abdelaal1, Andrew Carter, Sotiris Kyriakou, David Tetard, Stephany Veuger
1Northumbria University

Abstract

Background

Iron has been shown to drive cancer cell proliferation and survival through its role as an enzyme cofactor of ribonucleotide reductase. This has led to the investigation of iron chelators, which deplete cancer cells of their iron supply, as a potential anticancer therapy. NDRG1 is a crucial target of iron chelators, which inhibits key oncogenic signalling pathways such TGF-beta and Wnt/beta-catenin signalling. Our team has designed the novel iron chelator- SK4, which gains cell entry through LAT1; an amino acid transporter overexpressed in malignant tumours, thus enhancing selectivity to cancer cells. We have validated the mode of entry and action through control compounds each lacking a key moiety. Pathways associated with NDRG1 were analysed using gene expression data omnibus datasets elucidating the impact of NDRG1 on oncogenic signalling.

Method

We utilised Sulphorhodamine B assay and trypan blue staining to investigate growth inhibition and cell viability respectively. DAPI staining and Epifluorescent microscopy were used to determine apoptosis/necrosis levels. Meta-analysis was performed on MetaVolcanoR. Pathway analysis was conducted via Reactome and Cytoscape.

Results

SK4 displayed selective cytotoxicity to cancer cells with an IC50 of 110-195uM in HeLa and DU145 cells and an IC50 of greater than 500uM in normal human dermal fibroblasts and normal prostate cells PNT1A. Lack of effect with control compounds SK4C1 and SK4C2 demonstrates that the metal chelator moiety is responsible for inducing cell death and amino acid moiety responsible for cell entry. Strikingly, cancer cells treated with SK4 underwent more significant changes in nuclear morphology than normal cells indicating SK4 is capable of selectively inducing cell death.  When used in combination with the PARP-1 inhibitor Rucaparib, greater than additive effects were seen. The meta-analysis shows changes in pathways linked to oncogenesis such as integrin signalling.

Conclusion

SK4 has shown potential as a targeted cancer therapy for tumours that overexpress LAT1 and has promise as a stand-alone therapy or in combination with PARP inhibitors. NDRG1 has an impact on many key oncogenic pathways – this warrants further study in vitro and in vivo.

Impact statement

 SK4 is the first iron chelator to target LAT1 overexpression, which is commonly associated with poor prognosis and metastasis,