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Apoptotic impact of alpha1-blockers on prostate cancer growth: a myth or an inviting reality?
Anastasios Tahmatzopoulos1, Natasha Kyprianou
1Division of Urology, Department of Surgery, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
Background:
Pharmacological manipulation or genetic targeting of the major apoptosis regulators, such as bcl-2, caspases, and inhibitors of apoptosis (IAPs), represent clinically attractive avenues towards effective therapeutic strategies for advanced prostate cancer. A wealth of evidence established the alpha(1)-adrenoceptor antagonists to be clinically effective in relieving the symptoms associated with benign prostatic hyperplasia (BPH) by relaxing prostatic smooth muscle tone. This action alone however does not fully account for the long-term clinical response to these drugs in BPH patients.
Methods:
Experimental and retrospective clinical studies provided new evidence supporting a differential growth-suppressing function of two alpha(1)-adrenoceptor antagonists against prostate cancer, independent of an alpha(1)-adrenoceptor mechanism.
Results:
The quinazoline-based antagonists, doxazosin and terazosin, induce apoptosis, inhibit cell adhesion to the extracellular matrix (by activating anoikis), and prevent cell invasion and migration of prostate tumor epithelial cells and vascular endothelial cells. Tamsulosin, a sulphonamide-based, clinically effective alpha(1)-adrenoceptor antagonist for BPH treatment, fails to exert a similar apoptotic action against prostate cells. Furthermore, at pharmacologically relevant doses, doxazosin suppresses benign and malignant prostate growth in in vivo experimental models. The effect is characterized by three intriguing features: (a) it is mediated by an alpha(1)-adrenoceptor-independent action, (possibly related to the quinazoline nucleus); (b) it is targeted at the apoptotic process without affecting cell proliferation; and (c) the elevated apoptotic index correlated with symptom score improvement in BPH patients.
Conclusions:
This evidence challenges conventional knowledge of the mechanism of action of alpha(1)-adrenoceptor antagonists, and points to a new therapeutic value for these drugs by providing a differential molecular basis for their anti-tumor efficacy. The present review focuses on the characterization of the apoptotic/anti-angiogenic effect of quinazoline-based alpha(1)-adrenoceptor antagonists against prostate cancer cells and discusses the clinical significance of this action in the prevention and treatment of prostate cancer.
Insights
Quinazoline-based alpha(1)-adrenoceptor antagonists like doxazosin show anti-cancer effects in prostate cells by inducing apoptosis, independent of their BPH treatment mechanism. This suggests a new therapeutic potential for these drugs in prostate cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Targeting apoptosis regulators is key for advanced prostate cancer therapy.
- Alpha(1)-adrenoceptor antagonists treat benign prostatic hyperplasia (BPH) by relaxing smooth muscle.
- Their full mechanism in BPH and potential in cancer are not fully understood.
Purpose of the Study:
- To investigate the differential growth-suppressing effects of alpha(1)-adrenoceptor antagonists on prostate cancer.
- To explore mechanisms beyond alpha(1)-adrenoceptor antagonism.
Main Methods:
- Experimental and retrospective clinical studies were analyzed.
- Investigated the effects of doxazosin, terazosin, and tamsulosin on prostate cancer cells.
- Assessed apoptosis, cell adhesion, invasion, and migration in in vivo models.
Main Results:
- Quinazoline-based antagonists (doxazosin, terazosin) induce apoptosis and inhibit prostate cancer cell invasion and migration.
- Tamsulosin, a sulphonamide-based antagonist, did not show similar apoptotic effects.
- Doxazosin suppressed prostate tumor growth in vivo via an alpha(1)-adrenoceptor-independent mechanism, targeting apoptosis.
Conclusions:
- Alpha(1)-adrenoceptor antagonists, particularly quinazoline-based ones, possess anti-tumor efficacy against prostate cancer.
- This efficacy is mediated by apoptosis induction and is independent of their BPH mechanism.
- These findings suggest a novel therapeutic application for alpha(1)-adrenoceptor antagonists in prostate cancer prevention and treatment.
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