The road to personalised anticancer therapy: utilizing the LAT1 transporter as a selective mode of iron deprivation
Session type: Poster / e-Poster / Silent Theatre session
Iron is a cofactor for DNA replication and repair enzymes making it essential for cancer cell survival and proliferation. This has lead to the investigation of iron chelators as a potential cancer therapy. We have designed a series of iron chelator compounds, which deplete the cancer cells from iron and induce reactive oxygen species. These compounds are made up of two components a metal binding moiety, which chelates iron, and an amino acid side chain, which allows cell entry of the compounds through the LAT1 transporter; an amino acid antiport that is overexpressed in several cancers.
We have screened the compounds for the EC50 on HeLa, HDF, PC3, PTN1 and DU145 cell lines using a sulforhodamine B assay, which is an NCI validated screen. The cells were stained with DAPI and analysed using an epifluorescent microscope to look for nuclear morphology changes. The levels of reactive oxygen species were assessed using dihydrorhodamine 123 staining and flow cytometry.
The compounds are selectively cytotoxic to the cancer cells in a dose-dependent manner. With EC50 in PTN1a of >1000uM versus 100uM in DU145, HeLa and PC3 cells, respectively. An increase in reactive oxygen species was observed in treated cells. In addition to this, treated cells underwent nuclear condensation, chromatin condensation, and nuclear fragmentation; all changes associated with apoptosis with more profound changes observed in the tumour cells versus the normal cells.
Our results demonstrate that our iron chelator compounds could be used as a potential targeted treatment for cancer patients due to their selective cytotoxicity to cancer cells and tolerability in normal cells. The compound mechanism of action is thought to be the induction of reactive oxygen species, which is triggering cell death.