Abstract
BackgroundCancer cells have increased levels of transferrin receptor and lower levels of ferritin, an iron deficient phenotype that has led to the use of iron chelators to further deplete cells of iron and limit cancer cell growth. As cancer cells also have increased reactive oxygen species (ROS) we hypothesized that a contrarian approach of enhancing iron entry would allow for further increased generation of ROS causing oxidative damage and cell death.MethodsA small molecule library consisting of ~11,000 compounds was screened to identify compounds that stimulated iron-induced quenching of intracellular calcein fluorescence. We verified the iron facilitating properties of the lead compound, LS081, through 55Fe uptake and the expression of the iron storage protein, ferritin. LS081-induced iron facilitation was correlated with rates of cancer cell growth inhibition, ROS production, clonogenicity, and hypoxia induced factor (HIF) levels.ResultsCompound LS081 increased 55Fe uptake in various cancer cell lines and Caco2 cells, a model system for studying intestinal iron uptake. LS081 also increased the uptake of Fe from transferrin (Tf). LS081 decreased proliferation of the PC-3 prostate cancer cell line in the presence of iron with a lesser effect on normal prostate 267B1 cells. In addition, LS081 markedly decreased HIF-1α and -2α levels in DU-145 prostate cancer cell line and the MDA-MB-231 breast cancer cell lines, stimulated ROS production, and decreased clonogenicity.ConclusionsWe have developed a high through-put screening technique and identified small molecules that stimulate iron uptake both from ferriTf and non-Tf bound iron. These iron facilitator compounds displayed properties suggesting that they may serve as anti-cancer agents.
Highlights
Cancer cells have increased levels of transferrin receptor and lower levels of ferritin, an iron deficient phenotype that has led to the use of iron chelators to further deplete cells of iron and limit cancer cell growth
As noted in the Method, compounds which enhanced the calcein fluorescence quenching induced by iron were considered to be iron facilitators while those that decreased fluorescence quenching were considered inhibitors of iron uptake
In the initial screening of the compounds obtained from ChemDiv thirty compounds exhibited negative values for Δ Fn, i.e. Δ Fn < -50% and were defined as iron facilitators including a number of hydrazone compounds
Summary
Cancer cells have increased levels of transferrin receptor and lower levels of ferritin, an iron deficient phenotype that has led to the use of iron chelators to further deplete cells of iron and limit cancer cell growth. Iron is an essential element required for many biological processes from electron transport to ATP production to heme and DNA synthesis with the bulk of the iron being in the hemoglobin of circulating red blood cells [1,2]. Too little iron leads to a variety of pleiotropic effects from iron deficiency anemia to abnormal neurologic development, while too much iron may result in organ damage including hepatic cirrhosis and myocardiopathies. The remainder of the iron incorporated into newly synthesized hemoglobin is derived from macrophages from catabolized senescent red blood cells. The uptake of iron for its final incorporation into hemoglobin or other ferriproteins requires 3 different transport pathways: intestinal iron absorption, iron release from macrophages, and iron uptake into erythroid precursors and other iron-requiring cells
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