Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Hypoxia is a key phenomenon in tumor behavior, selecting for resistance to apoptosis, conferring resistance to radiotherapy and chemotherapy, and also inducing angiogenic factors such as vascular endothelial growth factor (VEGF). Exochelins are naturally evolved iron chelators produced by Mycobacterium tuberculosis. Because iron chelation has been reported to activate the hypoxia-inducible factor (HIF), we investigated the effects of an exochelin [desferri-exochelin (DFE) 772SM] on this hypoxia-inducible pathway and downstream target genes. DFE induced HIF-1alpha and HIF-2alpha transcription factors regulating the hypoxic response in the breast tumor cell line MDA468. DFE was 10 times more potent and more rapid in onset of effect than the clinically used iron chelator deferoxamine. The expression of downstream hypoxia-responsive target genes VEGF and the proapoptotic protein NIP3 was activated by transcription. MDA468 proliferation was inhibited via HIF-independent pathways, related to other effects of iron chelation. DFE inhibited effects of VEGF on endothelial cell proliferation. DFE potentially could be useful in cancer therapy by inducing apoptosis via NIP3 in conjunction with other non-HIF-related growth inhibitory pathways and blocking endothelial proliferation despite the presence of VEGF.

Type

Journal article

Journal

Cancer Res

Publication Date

01/12/2002

Volume

62

Pages

6924 - 6927

Keywords

Adenocarcinoma, Angiogenesis Inhibitors, Animals, Basic Helix-Loop-Helix Transcription Factors, Breast Neoplasms, CHO Cells, Cell Division, Cricetinae, DNA-Binding Proteins, Deferoxamine, Endothelial Growth Factors, Endothelium, Vascular, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Intercellular Signaling Peptides and Proteins, Iron Chelating Agents, Lymphokines, Membrane Proteins, Nuclear Proteins, Peptides, Cyclic, Proto-Oncogene Proteins, Trans-Activators, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Proteins, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors