A mycobacterial iron chelator, desferri-exochelin, induces hypoxia-inducible factors 1 and 2, NIP3, and vascular endothelial growth factor in cancer cell lines.
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.
Chong
Tsung Wen
TW
Cancer Research United Kingdom, Molecular Oncology Laboratories, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.
Horwitz
Lawrence D
LD
Moore
John W
JW
Sowter
Heidi M
HM
Harris
Adrian L
AL
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D003676:Deferoxamine / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008222:Lymphokines / Q000096:biosynthesis*; D008565:Membrane Proteins / Q000096:biosynthesis*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators / Q000096:biosynthesis*; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1
D020533:Angiogenesis Inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D003676:Deferoxamine; D016228:Endothelial Growth Factors; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D007502:Iron Chelating Agents; D008222:Lymphokines; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010456:Peptides, Cyclic; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C090121:BNIP3 protein, human; C116838:BNIP3L protein, human; C497442:HIF1A protein, human; C410730:desferriexochelin 772SM