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Alpha1-adrenoceptor antagonists radiosensitize prostate cancer cells via apoptosis induction
David C Cuellar1, Juong Rhee, Natasha Kyprianou
1Division of Urology, The University of Maryland School of Medicine, Baltimore, USA.
Background:
Androgen-independent prostate cancer cells can undergo apoptosis in response to non-androgen ablative means such as ionizing radiation. Recent evidence documented the ability of alpha-adrenoceptor antagonists, a widely used medical therapy for the treatment of benign prostatic hypertrophy (BPH), to induce apoptosis in benign and malignant prostate cells. In this study, we evaluated the potential additive/synergistic apoptotic effect of alpha1-adrenoceptor antagonists with ionizing radiation against human prostate cancer cells in vitro.
Materials And Methods:
Androgen-independent human prostate cancer cells (PC-3) were treated with two alpha1-adrenoceptor antagonists, doxazosin and terazosin, for various periods of time prior to and after exposure to ionizing radiation. Apoptosis induction, cell viability and clonogenic assays were then performed to determine loss of clonogenic survival Hoechst staining was performed to detect the apoptotic morphology in prostate cancer cells and the temporal protein expression of the apoptosis regulators bax and caspase-3, was determined using Western blot analysis.
Results:
No significant difference in cell death of PC-3 cells was detected when either doxazosin or terazosin was combined with ionizing radiation. Terazosin treatment however, 24 hours prior to, or 24 hours post-irradiation resulted in a significant enhancement of radiation-induced loss of clonogenic survival compared to radiation alone (p<0.05). Furthermore, there was a further significant increase in apoptosis induction when cells were pre-treated with terazosin (15%), compared to treatment with radiation alone (6%). Western blot analysis revealed a significant increase in bax protein expression (but not caspase-3) in response to radiation, with no additional effect with the combination treatment (terazosin and ionizing irradiation) compared to radiation alone.
Conclusion:
This is the first study to document the ability of alpha1-adrenoceptor antagonists to enhance the apoptotic effect of ionizing radiation against human prostate cancer cells. As this alpha1-adrenoceptor-mediated elevation of the apoptotic threshold involves neither bax deregulation nor caspase-3 activation, a differential mechanism might be underlying this radiosensitizing effect. The present findings may have important clinical relevance in identifying a more effective therapeutic approach for androgen-independent prostate cancer based on the combined apoptotic effects of quinazoline-based alpha1-adrenoceptor-antagonsists and radiotherapy.
Insights
Alpha1-adrenoceptor antagonists, like terazosin, can enhance radiation-induced apoptosis in prostate cancer cells. This combination therapy may offer a novel approach for treating androgen-independent prostate cancer.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Androgen-independent prostate cancer (PCa) can be targeted by non-androgen ablative methods like ionizing radiation.
- Alpha1-adrenoceptor antagonists, used for benign prostatic hypertrophy (BPH), demonstrate apoptosis-inducing capabilities in prostate cells.
- Investigating the combined effects of alpha1-adrenoceptor antagonists and ionizing radiation is crucial for PCa treatment.
Purpose of the Study:
- To evaluate the additive or synergistic apoptotic effects of alpha1-adrenoceptor antagonists combined with ionizing radiation on human prostate cancer cells in vitro.
- To assess the impact of doxazosin and terazosin, in conjunction with ionizing radiation, on prostate cancer cell apoptosis and survival.
Main Methods:
- Human prostate cancer cells (PC-3) were treated with doxazosin or terazosin before and after ionizing radiation exposure.
- Apoptosis induction, cell viability, and clonogenic survival were assessed using Hoechst staining and Western blot analysis for bax and caspase-3.
- Temporal protein expression of apoptosis regulators was analyzed to understand the underlying mechanisms.
Main Results:
- Terazosin treatment, 24 hours pre- or post-irradiation, significantly enhanced radiation-induced loss of clonogenic survival (p<0.05).
- Pre-treatment with terazosin significantly increased apoptosis induction (15%) compared to radiation alone (6%).
- Western blot showed increased bax protein expression with radiation, but no additional effect from combination therapy; caspase-3 levels remained unchanged.
Conclusions:
- This study is the first to show alpha1-adrenoceptor antagonists enhance the apoptotic effects of ionizing radiation in human prostate cancer cells.
- The radiosensitizing effect appears to involve mechanisms other than bax deregulation or caspase-3 activation.
- Combined therapy with quinazoline-based alpha1-adrenoceptor antagonists and radiotherapy presents a promising strategy for androgen-independent prostate cancer.