Alpha1-adrenoceptor antagonists radiosensitize prostate cancer cells via apoptosis induction.
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.


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.


CONCLUSIONS
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.
Cuellar
David C
DC
Division of Urology, The University of Maryland School of Medicine, Baltimore, USA.
Rhee
Juong
J
Kyprianou
Natasha
N
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D017292:Doxazosin / Q000494:pharmacology; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D011224:Prazosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D011838:Radiation-Sensitizing Agents; C041226:Terazosin; D017292:Doxazosin; D011224:Prazosin