title: Diaminothiazoles inhibit angiogenesis efficiently by suppressing Akt phosphorylation.
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.
authors.affiliation: Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, India.
authors.forename: Sannu A
authors.initials: SA
authors.lastname: Thomas
authors.forename: Reshma
authors.initials: R
authors.lastname: Thamkachy
authors.forename: Bindu
authors.initials: B
authors.lastname: Ashokan
authors.forename: Reena J
authors.initials: RJ
authors.lastname: Komalam
authors.forename: Keerthi V
authors.initials: KV
authors.lastname: Sreerekha
authors.forename: Asha
authors.initials: A
authors.lastname: Bharathan
authors.forename: Thankayyan R
authors.initials: TR
authors.lastname: Santhoshkumar
authors.forename: Kallikat N
authors.initials: KN
authors.lastname: Rajasekharan
authors.forename: Suparna
authors.initials: S
authors.lastname: Sengupta
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles; D014230:Triazoles / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000633:toxicity
chemical_list: C496402:4-amino-5-benzoyl-2-(4-methoxyphenylamino)thiazole; D020533:Angiogenesis Inhibitors; D013844:Thiazoles; D014230:Triazoles; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt; D018844:Cyclin-Dependent Kinases