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N Kyprianou

Publications and source records attributed to N Kyprianou.

At least 19 recordsLinked to original sources
PubMed2005

Human immunodeficiency virus-1 Tat protein up-regulates interleukin-6 and interleukin-8 expression in human breast cancer cells.

OBJECTIVE: To examine whether HIV-1 Tat protein increases the metastatic potential of human breast cancer cells through induction of pro-inflammatory tumor microenvironment. METHODS: Real-time RT-PCR and ELISA were employed to determine the mRNA and protein expression of IL-6 and IL-8 in highly metastatic human breast cancer cell line, MDA-MB-231. To investigate the transcriptional regulatory mechanisms of Tat-mediated up-regulation of IL-6 and IL-8, EMSA and reporter gene assay were carried out. RESULTS: Exposure of MDA-MB-231 cells to Tat resulted in a significant and dose-dependent up-regulation of IL-6 and IL-8 mRNA and protein expression. HIV-1 Tat protein also markedly increased NF-kappaB DNA-binding activity and transactivation in MDA-MB-231 cells. Additionally, pretreatment with NF-kappaB inhibitors significantly attenuated the ability of Tat to up-regulate IL-6 and IL-8 expression. It was also found that exposure of MDA-MB-231 cells to Tat induced up-regulation of MMP-9 expression at both mRNA and protein levels. CONCLUSIONS: These results suggest that HIV-1 Tat protein up-regulates expression of IL-6 and IL-8 in human breast cancer cells by NF-kappaB-dependent pathway. These data may contribute to exploration of the new molecular mechanisms leading to novel approaches for the therapeutic drug developments specifically targeted against the inflammatory pathways of breast cancer metastasis in AIDS patients.

Breast Neoplasms↗
PubMed2005

Apoptotic regulators in prostatic intraepithelial neoplasia (PIN): value in prostate cancer detection and prevention.

Early diagnosis of prostate cancer holds tremendous promise for the effective therapy and impact on survival of prostate cancer patients. High-grade prostatic intraepithelial neoplasia (HGPIN) is generally accepted as a lesion indicative of a late pathological event in the premalignant changes leading to full development of prostate cancer. This review seeks to identify specific molecular events that may be linked directly to the molecular transition from benign prostate epithelial cells to prostate carcinoma. HGPIN is pathologically detected in a limited group of men undergoing prostate cancer screening for an elevated serum prostate-specific antigen (PSA) or abnormal digital rectal examination (DRE). Loss of apoptotic control provides a molecular basis for the contribution of specific defective steps in the pathway towards development and progression of prostate cancer. Comparative dissection of the apoptosis status and expression profile of key apoptotic regulators among foci of highly proliferative benign prostatic epithelium, PIN and prostate adenocarcinoma from adjacent areas of the same gland revealed a novel insight into the dysfunctional apoptosis events contributing to prostate carcinogenesis. The sequential and notable loss of the three critical signaling components of the apoptotic action of transforming growth factor-beta (TGF-beta), in the prostate, that is, the transmembrane receptor II (TbetaRII), the key cell cycle inhibitor p27(Kip1), as well as the protagonist downstream effector of the TGF-beta signaling mechanism, Smad4, points to their potential value to 'faithfully' characterize HGPIN, as a premalignant prostate lesion. Recent evidence on the molecular changes in apoptosis regulators contributing to HGPIN and their role as molecular markers of disease onset, as well as candidates for therapeutic targeting/chemoprevention of prostate cancer in its early stages will be discussed.

Adenocarcinoma↗
PubMed2003

Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction.

Previous studies documented the ability of quinazoline-based alpha1-adrenoceptor antagonists to induce apoptosis in prostate cancer cells via an alpha 1-adrenoceptor-independent mechanism. In this study we investigated the molecular events initiating this apoptotic effect. Since transforming growth factor-beta 1 (TGF-beta 1) mediates prostate epithelial cell apoptosis, we hypothesised that the activation of the TGF-beta 1 pathway underlies the quinazoline-based apoptotic effect in prostate cancer cells. Treatment of the androgen-independent human prostate cancer cells PC-3 with doxazosin resulted in a strong caspase-3 activation within 24 h, whereas tamsulosin, a sulphonamide-based alpha 1-adrenoceptor antagonist, had no significant apoptotic effect against prostate cancer cells. To identify the molecular components involved in this quinazoline-mediated apoptosis, cDNA microarray analysis of PC-3 prostate cancer cells treated with doxazosin (3 h) was performed. Induced expression of several genes was observed including p21(WAF-1) and I kappa B alpha (inhibitor of NF-kappa B alpha). Relative quantitative reverse transcription-polymerase chain reaction analysis revealed induction of several TGF-beta1 signalling effectors: Induction of mRNA for Smad4 and the TGF-beta1-regulated apoptosis-inducing transcription factor TGF-beta1-inducible early gene (TIEG1) was detected within the first 6 h of doxazosin treatment. Upregulation of I kappa B alpha at both the mRNA and protein level was also detected after 6 h of treatment. Furthermore, doxazosin resulted in a considerable elevation in Smad4 and TIEG protein expression (6 h). A 'latent' increase in TGF-beta mRNA expression was detected after 48 h of treatment. These findings suggest that the quinazoline-based doxazosin mediates prostate cancer apoptosis by initially inducing the expression of TGF-beta1 signalling effectors and subsequently I kappa B alpha. The present study provides an initial insight into the molecular targets of the apoptotic action of quinazolines against prostate cancer cells.

AMP-Activated Protein Kinase Kinases↗
PubMed2002

Induction of prostate apoptosis by alpha1-adrenoceptor antagonists: mechanistic significance of the quinazoline component.

alpha(1)-Adrenoceptor antagonists, have been documented to induce apoptosis and reduce prostate tumor vascularity in benign and malignant prostate cells. The quinazoline based alpha(1)-antagonists, doxazosin and terazosin but not tamsulosin (a sulphonamide derivative) suppress prostate growth without affecting cell proliferation. These quinazoline-mediated apoptotic effects occur via an alpha(1)-adrenoceptor independent mechanism potentially involving activation of the TGF-beta signal transduction pathway. This review discusses the current knowledge of the action of quinazoline-derived alpha(1)-adrenoceptor antagonists in the benign and malignant prostate and their potential therapeutic use in the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. Finally, a molecular pathway is proposed for their observed apoptotic function against prostate cells. Increased understanding of the action of these established and clinically accepted agents would provide a basis for the design of safe, effective therapeutic regimens in the treatment of prostatic diseases.

Adrenergic Antagonists↗
PubMed2001

Reduction of human prostate tumor vascularity by the alpha1-adrenoceptor antagonist terazosin.

BACKGROUND: We previously demonstrated that the quinazoline-derived a1-adrenoceptor antagonists doxazosin and terazosin suppress prostate cancer growth via apoptosis induction. The aim of this study was to determine the potential effect of a1-adrenoceptor antagonists on tumor vascularity of the human prostate. METHODS: A total of 34 men with benign prostatic hyperplasia (BPH) who have been on terazosin treatment (for the obstructive symptoms) were pathologically diagnosed with prostate cancer following surgery. These patients were stratified according to the length of treatment periods with terazosin into two groups, 1 week-6 months, and 6-17 months. The control group consisted of prostatectomy specimens from 25 untreated prostate cancer patients undergoing surgery for localized disease. Formalin-fixed, paraffin-embedded prostate specimens were analyzed for apoptosis (TUNEL assay), cell proliferation (Ki-67), microvessel density (MVD) (von Willebrand factor/Factor VIII), vascular endothelial growth factor (VEGF) expression, and prostate specific antigen (PSA) immunoreactivity. RESULTS: A significant induction of apoptosis was observed among cancerous prostatic epithelial cells in the terazosin-treated, as compared to the untreated prostate cancer specimens, while there was no significant change in the proliferative index of the same tumor cell populations after treatment. Furthermore, terazosin resulted in a significant decrease in prostate tissue MVD compared with the untreated group (P < 0.01), that correlated with the increased apoptotic index of the cancerous areas. Tissue PSA expression in the prostatic tumor foci was also markedly reduced after terazosin treatment, while no significant changes in VEGF expression were detected. CONCLUSIONS: These findings provide the first evidence that terazosin, a quinazoline-based a1-blocker decreases prostate tumor vascularity. Our study has significant clinical implications in identifying selected alpha1-adrenoceptor antagonists as potential anti-tumor agents with apoptotic and anti-angiogenic effects in the human prostate that can be exploited for the treatment of advanced prostate cancer.

Adrenergic alpha-Antagonists↗
PubMed2001

Loss of caspase-1 and caspase-3 protein expression in human prostate cancer.

Activation of the caspase cascade is involved in the execution of apoptosis in a variety of cellular systems. Recent studies demonstrated that caspase-1 activation was required for human prostate cancer cells to undergo apoptosis in response to transforming growth factor-beta (Y. Guo and N. Kyprianou, Cancer Res., 59: 1366-1371, 1999). In the present study, to identify the significance of caspases in prostate cancer progression, we examined the expression of three key caspases, caspase-1, caspase-3, and caspase-9, in normal and malignant human prostates. Caspase-1, -3, and -9 expression was examined at the mRNA and the protein level in a series of human normal and malignant prostate specimens. No significant differences were observed in the mRNA expression in prostatic tumors relative to the normal gland for any of the three caspases. Immunohistochemical analysis revealed that the pattern of protein expression and distribution was uniformly homogeneous in the normal prostate, with the epithelial cells exhibiting a diffuse cytoplasmic staining for caspase-1 and caspase-3. Significantly, the majority of primary prostate cancer specimens (80%) had total lack of caspase-1 immunoreactivity, whereas the remaining showed a significantly reduced expression compared with the normal prostate (P < 0.05). Caspase-3 expression was also reduced in moderately and poorly differentiated prostatic tumors compared with well-differentiated prostate adenocarcinomas and the normal prostate (P < 0.05). No significant correlation was found between the apoptotic index or Gleason grade and the pattern of caspase protein expression in the primary prostatic tumors analyzed. Western blot analysis revealed constitutive expression of the proenzyme forms of caspase-1, -3, and -9 in the human prostate cancer cell lines PC-3, DU-145, TSU-Pr1m and LNCaP, but caspase-1 expression was low in the less tumorigenic cell lines, DU-145 and LNCaP. These findings implicate the loss of caspase-1 protein as a potential step in the loss of apoptotic control during prostate tumorigenesis. This study suggests that the pattern of caspase-1 and -3 expression in prostatic tumors may have prognostic significance in disease progression.

Blotting, Western↗
PubMed2001

Combined effect of terazosin and finasteride on apoptosis, cell proliferation, and transforming growth factor-beta expression in benign prostatic hyperplasia.

BACKGROUND: Medical treatment of benign prostatic hyperplasia (BPH) targets relief of symptoms by causing either relaxation of the prostatic smooth muscle with alpha1 adrenergic blockade, or shrinkage of the gland with 5alpha-reductase inhibitors. We recently demonstrated that alpha1-blockers, such as terazosin, induce apoptosis in prostatic cells. In this study, we examined the combined effect of finasteride and terazosin on the rate of apoptosis and cellular proliferation to investigate their potential synergy at the cellular level. METHODS: Prostate specimens were obtained from men who were treated with either finasteride (n = 24), terazosin (n = 42), or combination therapy (n = 10) for varying time periods (1 week to 36 months) for the relief of the symptoms of BPH. The proliferative and apoptotic indices of both stromal and epithelial prostatic cell populations were determined. Antibodies against TGF-beta1 and TbetaRII were used to examine the immunoreactivity of TGF-beta1 and TbetaRII, respectively, in all prostate tissue sections. RESULTS: The apoptotic index in both prostate cell populations was significantly higher following the combination treatment compared to terazosin or finasteride alone. There were no significant changes in the rate of cellular proliferation with any treatment. Furthermore, there was a significant increase in TGF-beta1 expression in the prostates of patients treated with terazosin or combination therapy, while there was no change in TbetaRII expression. CONCLUSIONS: These results support the concept that induction of prostate apoptosis is a potential molecular mechanism underlying the combination effect of alpha1 blockade with 5alpha-reductase inhibitors in the effective treatment of BPH. The upregulation of TGF-beta1 implies a role for this ligand as an effector of apoptosis induction in response to alpha1-blockade or finasteride therapy of BPH patients.

Adrenergic alpha-Antagonists↗
PubMed2001

Apoptosis and bcl-2 expression in prostate cancer: significance in clinical outcome after brachytherapy.

PURPOSE: Radiation induced apoptosis of prostate cancer cells may have therapeutic and prognostic significance in patients treated with radiotherapy. We determined whether the ability of prostate tumor cells to undergo apoptosis has potential value for predicting the clinical response of patients with prostate cancer to brachytherapy. MATERIALS AND METHODS: A total of 76 patients with clinical stages T1 to 2 disease who were not receiving adjuvant therapy underwent transperineal implantation with 125iodine or 103palladium seeds and biopsy 7 to 23 months (median 12) after therapy. Nonresponders were classified using the American Society for Therapeutic Radiology and Oncology criteria. The apoptotic index was analyzed using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling assay in archived biopsy specimens from 76 treated and 19 matched pretreatment control patients. Serial sections of prostatic tumors were also evaluated for the expression of bax and bcl-2 proteins (apoptosis regulators) by immunohistochemical testing. RESULTS: A significant increase in the apoptotic index was detected in post-brachytherapy compared with pretreatment prostate specimens (3.1% versus 2%, p <0.05), as well as in patients with negative biopsy at followup compared with those with persistent malignancy (3.4% versus 1.8%, p = 0.02). In addition, there was a significant elevation in bcl-2 expression in prostatic tissue in patients with treatment failure compared with responders (30.5% versus 13.1%, p <0.05). CONCLUSIONS: To our knowledge this is the first study to establish a correlation of apoptosis induction and bcl-2 over expression with treatment outcome in patients with prostate cancer after brachytherapy. Our findings have significant clinical implications for identifying the value of the apoptotic index and bcl-2 expression in prostatic tumors for predicting the therapeutic response to brachytherapy.

Adenocarcinoma↗
PubMed2001

Future concepts in the medical therapy of benign prostatic hyperplasia.

The standard medical therapy for symptomatic benign prostatic hyperplasia is still alpha-blockers and 5alpha-reductase inhibitors. Ongoing studies demonstrate the long-term safety and efficacy of these two classes of therapeutic approaches. Although there have been no new Food and Drug Administration approved medical therapies for the treatment of benign prostatic hyperplasia over the past year, interest in and the use of phytotherapeutic agents continues to increase. In this review, we will discuss the developments that have occurred over the past year in the medical management of benign prostatic hyperplasia. In addition, we present ongoing efforts at our center to obtain a better understanding of and manipulate the apoptotic pathway as it pertains to the pathophysiology of benign prostatic hyperplasia.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2001

Dihydrotestosterone enhances transforming growth factor-beta-induced apoptosis in hormone-sensitive prostate cancer cells.

In this study, the potential interactions between dihydrotestosterone (DHT), a survival factor, and transforming growth factor-beta (TGF-beta), an apoptotic inducer, were examined in a derivative of the hormone-sensitive prostate cancer cell line LNCAP: The LNCaP TGF-beta receptor II cells, engineered to express TGF-beta receptor II, are sensitive to both DHT and TGF-beta. Surprisingly, when the LNCaP TGF-beta receptor II cells were treated with TGF-beta in the presence of physiological levels of DHT, both cell cycle arrest and apoptosis induction were significantly enhanced over TGF-beta alone. This effect temporally correlated with an increased expression of the cell cycle regulator p21 as well as the apoptotic executioner, procaspase-1, and a parallel down-regulation of the antiapoptotic protein, bcl-2. Expression of bax and caspase-3 proteins remained unchanged following treatment. Furthermore, apoptosis induction was suppressed by the caspase-1 inhibitor, z-YVAD, but not the caspase-3 inhibitor, z-DQMD, thus demonstrating the functional significance of increased procaspase-1 expression in TGF-beta-mediated apoptosis in prostate cancer cells. These results indicate that TGF-beta-mediated apoptosis can actually be enhanced by androgens through specific mechanisms involving cell cycle and apoptosis regulators and provide initial evidence on the ability of physiological levels of androgens to stimulate the intrinsic apoptotic potential of prostate cancer cells. Therefore, this study provides a molecular basis for the priming of prostate cancer cells for maximal apoptosis induction, during hormone- ablation therapy.

Apoptosis↗
PubMed2000

Suppression of human prostate cancer cell growth by alpha1-adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis.

Recent evidence from our laboratory has demonstrated that alpha1-adrenoceptor antagonists doxazosin and terazosin induced apoptosis in prostate epithelial and smooth muscle cells in patients with benign prostatic hypertrophy (BPH; J. Urol., 159: 1810-1815, 1998; J. Urol., 161: 2002-2007, 1999). In this study, we investigated the biological action of three alpha1-adrenoceptor antagonists, doxazosin, terazosin, and tamsulosin, against prostate cancer cell growth. The antigrowth effect of the three alpha1-adrenoceptor antagonists was examined in two human prostate cancer cell lines, PC-3 and DU-145, and a prostate smooth muscle cell primary culture, SMC-1, on the basis of: (a) cell viability assay; (b) rate of DNA synthesis; and (c) induction of apoptosis. Our results indicate that treatment of prostate cancer cells with doxazosin or terazosin results in a significant loss of cell viability, via induction of apoptosis in a dose-dependent manner, whereas tamsulosin had no effect on prostate cell growth. Neither doxazosin nor terazosin exerted a significant effect on the rate of cell proliferation in prostate cancer cells. Exposure to phenoxybenzamine, an irreversible inhibitor of alpha1-adrenoceptors, does not abrogate the apoptotic effect of doxazosin or terazosin against human prostate cancer or smooth muscle cells. This suggests that the apoptotic activity of doxazosin and terazosin against prostate cells is independent of their capacity to antagonize alpha1-adrenoceptors. Furthermore, an in vivo efficacy trial demonstrated that doxazosin administration (at tolerated pharmacologically relevant doses) in SCID mice bearing PC-3 prostate cancer xenografts resulted in a significant inhibition of tumor growth. These findings demonstrate the ability of doxazosin and terazosin (but not tamsulosin) to suppress prostate cancer cell growth in vitro and in vivo by inducing apoptosis without affecting cell proliferation. This evidence provides the rationale for targeting both drugs, already in clinical use and with established adverse-effect profiles, against prostatic tumors for the treatment of advanced prostate cancer.

Adrenergic alpha-1 Receptor Agonists↗
PubMed2000

Racial differences in prostate cancer growth: apoptosis and cell proliferation in Caucasian and African-American patients.

BACKGROUND: Epidemiologic evidence reveals striking racial differences in incidence and clinical behavior of prostate cancer among American men. In this study, we assessed the incidence of apoptosis and cell proliferation in prostate cancer specimens from African-American and Caucasian patients in an attempt to identify potential differences in tumor growth determinants between the two ethnic groups. METHODS: Apoptosis and cell proliferation were analyzed in archival paraffin-embedded prostatic tumors from 44 African-American and 35 Caucasian age-matched men who underwent radical prostatectomy for localized prostate cancer. Both groups had comparable preoperative prostate-specific antigen (PSA) levels, clinical stage, and Gleason scores, and neither group of patients received neoadjuvant therapy prior to surgery. Apoptotic status in prostate tumors was evaluated in situ, using the transferase deoxyuridine end labeling (TUNEL) assay, and the expression profile of two apoptotic proteins, bcl-2 and bax. The proliferative index was determined on the basis of Ki-67 antigen immunoreactivity. RESULTS: Apoptosis in malignant prostate cells was significantly higher in African American than Caucasian men (11.6% vs. 4.2%, P < 0. 001). Interestingly, the rate of cell proliferation of prostate tumor cells was similar in the two ethnic groups (4.5% and 4.2%). The antiapoptotic protein bcl-2 was detected at significantly higher levels in tumors from Caucasian than African-American patients (40. 8% vs. 31.6%, P < 0.05). Expression of bax, the apoptosis promoter, was consistently high among tumor epithelial cells in specimens from both racial groups (68%). CONCLUSIONS: These findings provide a novel insight into the molecular determinants of tumor growth that may underlie the ethnic differences in prostate cancer incidence and clinical behavior. Downregulation of bcl-2 expression may be potentially responsible for the loss of apoptotic control in prostate tumors from African-American men. This study may have significant clinical implications in the development of novel diagnostic approaches for biologically aggressive prostate cancer from diverse racial origin.

Aged↗
PubMed2000

Effects of alpha(1)-adrenoceptor (alpha(1)-AR) antagonists on cell proliferation and apoptosis in the prostate: therapeutic implications in prostatic disease.

BACKGROUND: Benign prostate hyperplasia (BPH) and prostate cancer established that disruption of the molecular mechanisms that regulate apoptosis and cell proliferation among the stromal and epithelial cell populations, may underlie the neoplastic development that characterizes the aging gland. This work examined the effects of selected alpha(1)-adrenoceptor (alpha(1)-AR) antagonists (blockers) on cellular dynamics to determine whether induction of apoptosis or inhibition of proliferation could contribute to the overall clinical profile. METHODS: Our efforts were focused on investigating whether alpha(1)-AR antagonists of two different chemical classes affect prostate pathophysiology via mechanisms other than smooth muscle contraction. In in vitro experiments, the two clinically used quinazoline alpha(1)-adrenoceptor antagonists terazosin and doxazosin and the chemically-distinct sulphonamide, tamsulosin, were examined for effects on prostatic tumor growth, by inhibiting cell proliferation and'or inducing apoptosis. RESULTS: Our findings suggest that alpha(1)-AR antagonists, terazosin and doxazosin, suppress prostatic growth by inducing apoptosis in a dose-dependent manner and without affecting cell proliferation. Tamsulosin exerted no effect on prostate cancer cell growth. The apoptotic effect of terazosin and doxazosin appears to be independent of the alpha(1)-adrenoceptor block. CONCLUSIONS: Taken together, our findings demonstrate the ability of the quinazoline alpha-blockers, terazosin and doxazosin, but not the sulphonamide, tamsulosin, to suppress prostate growth by inducing apoptosis among the epithelial cells in the benign and malignant prostate. These studies underwrite the durability of the response seen in long-term studies with terazosin, and suggest the potential of this drug in the treatment of prostate carcinoma.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2000

Apoptosis in prostate carcinogenesis. A growth regulator and a therapeutic target.

Development of effective therapeutic modalities for the treatment of human cancer relies heavily upon understanding the molecular alterations that result in initiation and progression of the tumorigenic process. Many of the molecular changes identified in human prostate tumorigenesis so far play key roles in apoptosis regulation. Apoptosis represents a universal and exquisitely efficient cellular suicide pathway. Since the therapeutic goal is to trigger tumor-selective apoptotic cell death (without clinically significant effects on the host), elucidation of the mechanisms underlying apoptosis deregulation will lead to the identification of specific cellular components for targeting therapeutic interventions. As our understanding of its vital role in the development and growth of the prostate gland has expanded, numerous genes that encode apoptotic regulators have been identified that are severely impaired in prostate cancer cells. In addition, the expression of apoptotic modulators within prostatic tumors appears to correlate with tumor sensitivity to traditional therapies such as hormonal ablation and radiotherapy. No strict correlation between apoptosis induction and a patient's long-term prognosis has emerged, perhaps due to the fact that the ability to achieve initial remission alone does not adequately predict long-term outcome. This review will encompass the known molecular changes intimately involved in the apoptotic pathway which have potential prognostic value in disease progression, as well as therapeutic significance in the enhancement of the apoptotic response to novel and established treatment strategies for the treatment of androgen-dependent and androgen-independent prostatic tumors. The main focus will be on the role of the transforming growth factor-beta (TGF-beta) signaling pathway, bcl-2 and the bcl-2 family members, the caspase cascade (apoptosis executioners), and the Fas pathway in induction and regulation of apoptosis following therapeutic stimuli for the management of advanced prostate cancer.

Animals↗
PubMed2000

Induction of apoptosis in the prostate by alpha1-adrenoceptor antagonists: a novel effect of "old" drugs.

Advances in our understanding of the integrated functions governing prostate cell proliferation and cell death imply that effective therapies for prostate neoplasia should not only be molecularly targeted, but should be customized to take into account the delicate balance of opposing growth influences. Evidence from studies on the dynamics of prostate growth in benign prostatic hyperplasia (BPH) and prostate cancer established that disruption of the molecular mechanisms that regulate apoptosis and cell proliferation among the stroma and epithelial cell populations may underlie the neoplastic development that characterizes the aging gland. Our own efforts have been focused on investigating whether a1-adrenoceptor antagonists clinically used for the relief of the obstructive symptoms associated with BPH affect prostate pathophysiology via mechanisms other than smooth muscle contraction. Such efforts led to the identification of a novel effect of two alpha1-adrenoceptor antagonists, doxazosin and terazosin. More recent in vitro experiments examined the potential anti-tumor action of three clinically used alpha1-adrenoceptor antagonists--doxazosin, terazosin and tamsulosin--against prostate cancer cell growth. These findings demonstrate the ability of doxazosin and terazosin, but not tamsulosin, to suppress prostate growth by inducing apoptosis among the epithelial cells in the benign and malignant prostate. Thus, evidence indicates that rather than just causing pure relaxation of the smooth muscle, certain alpha1-blockers can also affect the dynamics of prostate growth by changing the balance between prostate cell proliferation and apoptosis at the expense of the proliferative process.

Adrenergic alpha-Antagonists↗
PubMed2000

Cell proliferation and apoptosis in prostate cancer: significance in disease progression and therapy.

Recent biochemical and genetic studies have substantially increased our understanding of death signal transduction pathways, making it clear however, that apoptosis is not a single-lane, one-way street. Rather, multiple parallel pathways have been identified. For instance, analysis of bcl-2, bax, p53, and caspase knockout mice while establishing distinct roles for each of these apoptotic players, they also provided valuable information for the design of specific inhibitors of apoptosis. Thus blocking one pathway, as in caspase knockout mice, what we observe is not a complete suppression of apoptosis but rather a delay in apoptosis induction (Hakem et al., 1998; Kuida et al., 1998). In view of nature's means of ensuring activation of a compensatory apoptotic response, when one pathway fails in developing prostate cancer therapeutic interventions, the challenge remains to further dissect individual apoptotic pathways. Advances in our understanding of the integrated functions governing prostate cell proliferation and cell death, clearly suggest that effective prostate cancer therapies are not only molecularly targeted, but that are also customized to take into account the delicate balance of opposing growth influences in the ageing gland. In this review we discuss the evidence on the significance of molecular deregulation of the key players of this growth equilibrium, apoptosis and cell proliferation in prostate cancer progression, and the clinical implications of changes in the apoptotic response in disease detection and therapy.

Animals↗
PubMed1999

Restoration of transforming growth factor beta signaling pathway in human prostate cancer cells suppresses tumorigenicity via induction of caspase-1-mediated apoptosis.

Previous studies (Y. Guo and N. Kyprianou, Cell Growth Diff., 9: 185-193, 1998) have demonstrated that overexpression of transforming growth factor (TGF) beta type II receptor (TbetaRII) gene in human prostate cancer cells LNCaP, which are refractory to TGF-beta1 and lack TbetaRII receptor expression, can restore TGF-beta1 sensitivity and suppress in vitro tumorigenic growth by inhibiting cell proliferation. In the present study, we investigated the effect of TbetaRII receptor overexpression in LNCaP cells on apoptosis induction and tumorigenicity. The ability of LNCaP cells that overexpress TbetaRII to undergo apoptosis in response to TGF-beta1 was examined by DNA fragmentation and terminal transferase-mediated dUTP-biotin end labeling analysis. To explore the potential apoptotic nature of TGF-beta1-mediated antitumor effect against human prostate cancer cells, the expression of apoptotic proteins bcl-2 and bax was examined by Western blot analyses. The significance of caspase 1 in TGF-beta1-mediated apoptosis was also determined by examining the expression and activation of caspase 1 by reverse transcription-PCR and Western blot analyses, respectively. Comparative analysis of tumorigenicity of the parental LNCaP and TbetaRII-overexpressing clones in severely combined immunodeficient mice revealed a significant suppression of tumor growth in TbetaRII transfectant clones compared with parental LNCaP cells and neomycin-control clones (P < 0.05). A significantly higher incidence of endogenous apoptosis was observed in TbetaRII clone-61-derived tumor compared with the parental LNCaP tumors. This induction of apoptosis in the LNCaP tumors with restored TGF-beta1 signaling was associated with decreased bcl-2 expression, increased bax, and caspase-1 immunoreactivty. Moreover, an increased expression of the cyclin-dependent kinase inhibitor p27Kip1 was detected in TbetaRII-overexpressing tumors compared with the parental tumors. LNCaP TbetaRII transfectant cells exhibited a marked induction of apoptosis, paralleled with a decreased bcl-2 expression in response to TGF-beta1 treatment in vitro. This TGF-beta1-mediated apoptosis induction in TbetaRII transfectant cells was significantly protected by the caspase-1 inhibitor (zVAD-fmk) in a dose-dependent manner. Furthermore, a significant temporal induction of caspase-1 mRNA and protein expression was detected in TbetaRII cells in response to TGF-beta1 treatment. Our findings suggest that restoration of TGF-beta1 signaling suppresses tumorigenicity of human prostate cancer cells by inducing apoptosis, potentially via a caspase-1-mediated pathway.

Animals↗