Abstract
The prevention of neovessel formation or angiogenesis is a recent popular strategy for limiting and curing cancer. Diaminothiazoles are a class of compounds that have been reported to show promise in the treatment of cancer by inhibiting cancer cell proliferation and inducing apoptosis, because of their effects on microtubules and as inhibitors of cyclin-dependent kinases. Many microtubule-targeting agents are being studied for their antiangiogenic activity, and a few have shown promising activity in the treatment of cancer. Here, we report that diaminothiazoles can be highly effective as antiangiogenic agents, as observed in the chick membrane assay. The lead compound, 4-amino-5-benzoyl-2-(4-methoxyphenylamino)thiazole (DAT1), inhibits endothelial cell processes such as invasion, migration, and tubule formation, which require a functional cytoskeleton. DAT1 also decreases the expression of cell adhesion markers. The antiangiogenic activities of DAT1 occur at concentrations that are not cytotoxic to the normal endothelium. Analysis of intracellular signaling pathways shows that DAT1 inhibits Akt phosphorylation, which is actively involved in the angiogenic process. The antiangiogenic properties of diaminothiazoles, in addition to their promising antimitotic and cytotoxic properties in cancer cell lines, give them an extra advantage in the treatment of cancer.
Footnotes
This work was supported by the Department of Science and Technology, Government of India; Rajiv Gandhi Centre for Biotechnology core funding from the Department of Biotechnology and the Council of Scientific and Industrial Research, University Grants Commission, Government of India; and the Kerala State Council for Science, Technology, and Environment, Government of Kerala (fellowships to S.A.T., R.T., R.J.K., and K.V.S.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- VEGF
- vascular endothelial growth factor
- HUVEC
- human umbilical vein endothelial cell
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- LY294002
- 2-(4-morpholinyl)-8-phenyl-chromone
- DAT1
- 4-amino-5-benzoyl-2-(4-methoxyphenylamino)thiazole
- CA4P
- combretastatin A4 phosphate
- VWF
- von Willebrand factor
- Ac-LDL
- acetylated low-density lipoprotein
- Dil
- 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate
- PI3K
- phosphatidylinositol 3-kinase
- PBS
- phosphate-buffered saline
- FBS
- fetal bovine serum.
- Received January 27, 2012.
- Accepted March 12, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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