Novel quinazoline-based compounds impair prostate tumorigenesis by targeting tumor vascularity.
Previous evidence showed the ability of the quinazoline-based alpha(1)-adrenoreceptor antagonist doxazosin to suppress prostate tumor growth via apoptosis. In this study, we carried out structural optimization of the chemical nucleus of doxazosin and a subsequent structure-function analysis toward the development of a novel class of apoptosis-inducing and angiogenesis-targeting agents. Our lead compound, DZ-50, was effective at reducing endothelial cell viability via a nonapoptotic mechanism. Treatment with DZ-50 effectively prevented in vitro tube formation and in vivo chorioallantoic membrane vessel development. Confocal microscopy revealed a significantly reduced ability of tumor cells to attach to extracellular matrix and migrate through endothelial cells in the presence of DZ-50. In vivo tumorigenicty studies using two androgen-independent human prostate cancer xenografts, PC-3 and DU-145, showed that DZ-50 treatment leads to significant suppression of tumorigenic growth. Exposure to the drug at the time of tumor cell inoculation led to prevention of prostate cancer initiation. Furthermore, DZ-50 resulted in a reduced formation of prostate-tumor derived metastatic lesions to the lungs in an in vivo spontaneous metastasis assay. Thus, our drug discovery approach led to the development of a class of lead (quinazoline-based) compounds with higher potency than doxazosin in suppressing prostate growth by targeting tissue vascularity. This new class of quinazoline-based compounds provides considerable promise as antitumor drugs for the treatment of advanced prostate cancer.
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
Jason B
JB
Garrison
Yeng-Jeng
YJ
Shaw
Ching-Shih
CS
Chen
Natasha
N
Kyprianou
D000317:Adrenergic alpha-Antagonists / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000187:drug effects / Q000378:metabolism; D017292:Doxazosin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000737:chemistry / Q000627:therapeutic use*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
C525921:2-(4-(biphenyl-4-sulfonyl)-piperazin-1-yl)-6,7-dipropoxyquinazolin-4-yl-amine; D000317:Adrenergic alpha-Antagonists; D019012:Integrin beta1; D011799:Quinazolines; D017292:Doxazosin