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.
Garrison
Jason B
JB
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
Shaw
Yeng-Jeng
YJ
Chen
Ching-Shih
CS
Kyprianou
Natasha
N
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