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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Antiangiogenic hypoxic cytotoxin TX-402 inhibits hypoxia-inducible factor 1 signaling pathway.

BACKGROUND: Hypoxia represents an important tumor-specific target for cancer therapy. We have reported that hypoxic cytotoxins, such as TX-1102, tirapazamine (TPZ) and TX-402, selectively induced tumor cells to p53-independent apoptosis under hypoxic conditions and inhibited angiogenesis. MATERIALS AND METHODS: We investigated the effects of the antiangiogenic hypoxic cytotoxins on hypoxia-induced gene expression and their hypoxia-selective cytotoxicity in human squamous cell carcinoma of the head and neck (SAS cells) and p53-deficient human non-small cell lung carcinoma H1299 cells transfected with either wild-type or mutant p53 gene. RESULTS: TX-402 had more potent hypoxia-selective cytotoxicity than TPZ in either cell regardless of p53 status. All the compounds inhibited angiogenesis potently at doses of more than 5 micrograms/CAM in chick embryo chorioallantoic membrane (CAM) assay. RT-PCR analyses indicated that TX-402 reduced the inducible expression of vascular endothelial cell growth factors (VEGF) and glucose transporter type 3 (GLUT-3) under hypoxic conditions selectively. The mRNA and protein expression of HIF-1 alpha were also suppressed by TX-402 at the same time. CONCLUSION: The potent antiangiogenic effects of hypoxic cytotoxins can be attributed to the suppression of VEGF and HIF-1 induction through the hypoxia-inducible pathway. We show an other aspect of the hypoxic cytotoxin as an HIF-1 inhibitor for hypoxia-targeted therapy to improve cancer treatment and prognosis.[1]

References

  1. Antiangiogenic hypoxic cytotoxin TX-402 inhibits hypoxia-inducible factor 1 signaling pathway. Nagasawa, H., Mikamo, N., Nakajima, Y., Matsumoto, H., Uto, Y., Hori, H. Anticancer Res. (2003) [Pubmed]
 
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