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.

• Authors: P M Pahl, M A Horwitz, K B Horwitz, L D Horwitz
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 69 Issue 1 Pg. 69-79 (Sep 2001) ISSN: 0167-6806 [Print] Netherlands
• PMID: 11759830 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Iron Chelating Agents
• Peptides, Cyclic
• desferriexochelin 772SM

Topics

• Apoptosis
• Breast (cytology)
• Breast Neoplasms (pathology)
• Cell Division
• Dose-Response Relationship, Drug
• Female
• Humans
• Iron Chelating Agents (pharmacology)
• Peptides, Cyclic (pharmacology)
• Tumor Cells, Cultured