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.


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.


CONCLUSIONS
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.
Nagasawa
Hideko
H
Department of Biological Science and Technology, Faculty of Engineering, University of Tokushima, Minimijosanjimacho-2, Tokushima 770-8506, Japan.
Mikamo
Naoko
N
Nakajima
Yoshimi
Y
Matsumoto
Hideki
H
Uto
Yoshihiro
Y
Hori
Hitoshi
H
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D000077704:Tirapazamine; D014157:Transcription Factors; D014162:Transfection; D014227:Triazines / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D014227:Triazines; D000077704:Tirapazamine