Desferri-exochelin induces death by apoptosis in human breast cancer cells but does not kill normal breast cells.
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.
Pahl
P M
PM
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.
Horwitz
M A
MA
Horwitz
K B
KB
Horwitz
L D
LD
D017209:Apoptosis; D001940:Breast / Q000166:cytology*; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D007502:Iron Chelating Agents; D010456:Peptides, Cyclic; C410730:desferriexochelin 772SM