Desferri-exochelin induces death by apoptosis in human breast cancer cells but does not kill normal breast cells

Abstract

A major goal of cancer chemotherapy is the identification of cytotoxic compounds that are highly selective for cancer cells. We describe here one such compound - a novel iron chelator, desferri-exochelin 772SM. This desferri-exochelin has unique chemical and pharmacological properties, including extremely high iron binding affinity, the capacity to block iron-mediated redox reactions, and lipid solubility which enables it to enter cells rapidly. At low concentrations, this desferri-exochelin kills T47D-YB and MCF-7 human breast cancer cells by inducing apoptosis, but only reversibly arrests the growth of normal human mammary epithelial cells without cytotoxicity. Since iron-loaded exochelin is ineffective, iron chelation accounts for the efficacy of desferri-exochelin. For both the killing of breast cancer cells and the growth arrest of normal breast epithelial cells, desferri-exochelin was effective at much lower concentrations than the lipid-insoluble iron chelator deferoxamine, which has shown only limited potential as an anti-cancer agent. Growth arrest of progesterone receptor positive T47D-YB cells with the progestin R5020 transiently protects them from the cytotoxic effects of desferri-exochelin, but the cells are killed after cell growth resumes. Similarly, MCF-7 cells arrested with the estrogen antagonist ICI182780 are transiently resistant to killing by desferri-exochelin. Thus the desferri-exochelin is cytotoxic only to actively growing tumor cells. Since desferri-exochelin 772SM can selectively and efficiently destroy proliferating cancer cells without damaging normal cells, it may prove useful for the treatment of cancer.

Effects of Transferrin Receptor Blockade on Cancer Cell Proliferation and Hypoxia-Inducible Factor Function and Their Differential Regulation by Ascorbate

“…Both these anti-TfR mAbs and other anti-TfR mAbs have been shown previously to have synergistic antiproliferative effects on human cell lines cells in vitro and inhibit the growth and induce tumor regressions of established s.c. tumors of CCRF-CEM leukemia cells in nude mice (17,34). Breast cancer cell lines have also been shown to express high levels of TfR compared with normal breast epithelial cells and are more sensitive to iron depletion, which leads to inhibition of cell proliferation (35)(36)(37). The synergistic inhibition of proliferation induced by two anti-TfR mAbs is likely related to the ability of the mAbs to bind to different epitopes in TfR, resulting in receptor cross-linking, and block in iron uptake, which is required for DNA synthesis (9,38).…”

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

“…No cytotoxicity was evident when normal human mammary epithelial cells were treated at 5 or 20 M, although a growth arrest was seen (Pahl et al, 2001). These effects were prevented when either cell line was incubated with the iron-loaded D-Exo, indicating that the iron-binding ability of this ligand was responsible for its antiproliferative activity (Pahl et al, 2001). Further studies examining D-Exo 772SM on DNA synthesis demonstrated a 95% to 97% reduction of [ 3 H]thymidine incorporation in both the normal and cancerous breast cell lines after a 6-h incubation (Pahl et al, 2001).…”

“…4) as an antiproliferative agent. An in vitro study examining the effect of 20 M D-Exo 772SM on MCF-7 breast cancer cells illustrated potent antineoplastic activity where all cells were killed after 4 days of treatment (Pahl et al, 2001). No cytotoxicity was evident when normal human mammary epithelial cells were treated at 5 or 20 M, although a growth arrest was seen (Pahl et al, 2001).…”

“…An in vitro study examining the effect of 20 M D-Exo 772SM on MCF-7 breast cancer cells illustrated potent antineoplastic activity where all cells were killed after 4 days of treatment (Pahl et al, 2001). No cytotoxicity was evident when normal human mammary epithelial cells were treated at 5 or 20 M, although a growth arrest was seen (Pahl et al, 2001). These effects were prevented when either cell line was incubated with the iron-loaded D-Exo, indicating that the iron-binding ability of this ligand was responsible for its antiproliferative activity (Pahl et al, 2001).…”

Competing pathways of iron chelation: Angiogenesis or anti‐tumor activity: Targeting different molecules to induce specific effects

“…14 Furthermore, the ligand was also shown to cause tumor cell death via inducing apoptosis. 15 It is also interesting to note that there are studies that suggest Fe is required for angiogenesis. Indeed, Carlevaro et al 16 demonstrated that the Fe-transport molecule, transferrin, is a major angiogenic stimulus released by hypertrophic cartilage.…”