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

Abstract

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.

• Authors: Hideko Nagasawa, Naoko Mikamo, Yoshimi Nakajima, Hideki Matsumoto, Yoshihiro Uto, Hitoshi Hori
• Journal: Anticancer research (Anticancer Res) 2003 Nov-Dec Vol. 23 Issue 6a Pg. 4427-34 ISSN: 0250-7005 [Print] Greece
• PMID: 14666730 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• DNA-Binding Proteins
• HIF1A protein, human
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nuclear Proteins
• Transcription Factors
• Triazines
• Tirapazamine

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Carcinoma, Non-Small-Cell Lung (blood supply, drug therapy, genetics)
• Cell Hypoxia (genetics)
• Cell Line, Tumor
• Chick Embryo
• DNA-Binding Proteins (antagonists & inhibitors)
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, p53
• Humans
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lung Neoplasms (blood supply, drug therapy, genetics)
• Nuclear Proteins (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Tirapazamine
• Transcription Factors
• Transfection
• Triazines (pharmacology)