Anoikis induction by quinazoline based alpha 1-adrenoceptor antagonists in prostate cancer cells: antagonistic effect of bcl-2.
OBJECTIVE
The ability of the quinazoline derived alpha1-adrenoceptor antagonists doxazosin and terazosin to induce apoptosis in benign and malignant prostate cells has been established. In this study we investigated the effect of the 2 piperazidinyl quinazoline based alpha1-adrenoceptor antagonists and the methoxybenzene sulfonamide alpha1-antagonist tamsulosin on human prostate cancer cell adhesion.


METHODS
Androgen independent PC-3 prostate cancer cells and PC-3 transfectant clones over expressing the apoptosis suppressor bcl-2 were used as an in vitro model. Cells were treated with pharmacologically relevant doses of 1 of the 3 alpha1-adrenoceptor antagonists and the effect on cell viability/cell adhesion on various substrates was examined. Analysis of expression of key attachment factors, such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-alpha, was performed.


RESULTS
Our results indicate a significant decrease in prostate cancer cell adhesion to gelatin and collagen but not to fibronectin in prostate cancer cells treated with doxazosin or terazosin (25 microM.) compared with untreated control cultures (p <0.05). In contrast, tamsulosin had no effect on prostate cancer cell adhesion. The 2 quinazolines doxazosin and terazosin but not tamsulosin had a significant inhibitory effect on prostate tumor cell invasion. In bcl-2 over expressing prostate cancer cells there was significant suppression of doxazosin induced anoikis and cell invasion compared with neocontrol transfectants (p <0.05). Doxazosin resulted in transient down-regulation (2-fold decrease) of VEGF at the mRNA and protein levels, as detected by reverse transcriptase-polymerase chain reaction and Western blotting, respectively. No significant changes in the expression profile of hypoxia inducible factor-1 alpha were observed after treatment with quinazolines. Furthermore, bcl-2 resulted in partial reversion of the doxazosin induced VEGF decrease.


CONCLUSIONS
These findings demonstrate that the quinazoline derived alpha1-antagonists doxazosin and terazosin but not sulfonamide based tamsulosin induce anoikis and inhibit prostate cancer cell invasion, an effect that is antagonized by bcl-2. This molecular basis of an alpha1-adrenoceptor independent action against prostate cancer cells by the quinazolines may have potential therapeutic significance in prostate cancer.
Keledjian
Kasapr
K
Divisionof Urology, University of Maryland, Baltimore, USA.
Kyprianou
Natasha
N
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D023102:Anoikis / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017292:Doxazosin / Q000494:pharmacology*; D016228:Endothelial Growth Factors / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D009361:Neoplasm Invasiveness; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D000077409:Tamsulosin; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C041226:Terazosin; D000077409:Tamsulosin; D017292:Doxazosin; D011224:Prazosin