Biomedical subjects

Jasmin Bektic

Publications and source records attributed to Jasmin Bektic.

At least 19 recordsLinked to original sources

PubMed2006

Regulation of growth of prostate cancer cells selected in the presence of interleukin-6 by the anti-interleukin-6 antibody CNTO 328.

BACKGROUND: Interleukin-6 (IL-6) is a multifunctional regulator of cellular events in prostate cancer. LNCaP-IL-6+ cells selected in the presence of IL-6 were taken for assessment of effects of the chimeric monoclonal anti-IL-6 antibody CNTO 328. METHODS: Cell viability was assessed after treatment with CNTO 328 by the ATP assay. Expression of Bcl-2 and Bax and activation of signaling pathways were evaluated by Western analysis. Nude mice were inoculated with LNCaP-IL-6+ cells and treated with CNTO 328. The tumors were analyzed by immunohistochemistry for expression of Ki-67, tissue transglutaminase, and vascular endothelial growth factor. RESULTS: CNTO 328 caused a statistically significant inhibition of cell viability. The protein levels of Bcl-2 and the phosphorylation of ERK1/2 mitogen-activated protein kinases were decreased by the anti-IL-6 antibody. Treatment with CNTO 328 yielded an increase in the phosphorylation of signal transducers and activators of transcription factor 3. The mean tumor volume in animals inoculated with LNCaP-IL-6+ cells and treated with CNTO 328 was insignificantly lower than that in animals treated with the control antibody. There was a statistically significant decrease in the percentage of Ki-67-positive cells in CNTO 328-treated tumors. CONCLUSION: CNTO 328 has a potential in prostate cancer therapy and could be further tested in various combination experimental treatments.

Animals↗

PubMed2006

Relapse after radical prostatectomy correlates with preoperative PSA velocity and tumor volume: results from a screening population.

OBJECTIVES: To evaluate, in a screening population, the impact of tumor volume and prostate volume on prostate-specific antigen (PSA) velocity (PSAV) and to find predictors of biochemical failure after radical prostatectomy. Longitudinal PSA changes in men with prostate cancer have been reported to be significantly different from those without prostate cancer. METHODS: PSAV was assessed in 102 men undergoing radical retropubic prostatectomy. The pathologic findings of specimens obtained at radical retropubic prostatectomy and pelvic lymph node dissection were analyzed separately for all patients. RESULTS: The median preoperative PSA in the 102 patients was 6.4 ng/mL, the median prostate volume was 32.8 cm3, and the median tumor volume was 1.27 cm3. The PSAV correlated significantly with tumor volume (P <0.05) but not with prostate volume (P = 0.142). The median tumor volume in men with biochemical progression after radical retropubic prostatectomy was 2.55 cm3 versus 0.94 cm3 in men who were free of disease 5 years after surgery. The median PSAV in the year before diagnosis in men with relapse after radical prostatectomy was 1.98 ng/mL/yr versus 1.05 ng/mL/yr in men who had no evidence of disease. CONCLUSIONS: The results of our study have shown that the main factor contributing to the PSAV in patients with prostate cancer is cancer load and that prostate volume is not significantly associated with the PSAV. Men with a PSAV of more than 2 ng/mL/yr in the year before cancer diagnosis are at a high risk of relapse. The PSAV may be helpful in identifying patients with small tumors and thus increase the detection rate of potentially curable prostate cancers.

Adult↗

PubMed2006

Vascular resistance in the prostate evaluated by colour Doppler ultrasonography: is benign prostatic hyperplasia a vascular disease?

OBJECTIVE: To evaluate prostatic vascular resistance by measuring the resistive index (RI), and flow velocity using colour Doppler ultrasonography (CDUS), in normal prostates and in patients with benign prostatic hyperplasia (BPH) or prostate cancer, as BPH is considered to be a result of urogenital ageing and studies suggest that hyperplasia in the stromal and glandular compartments might be induced by stromal growth secondary to hypoxia, which in turn results from abnormal blood flow patterns. PATIENTS, SUBJECTS AND METHODS: Ninety-two men (22 with normal prostates, 45 with BPH and 25 with prostate cancer; mean age 56 years) were prospectively evaluated by CDUS. The RI values for the peripheral, central and transition zones were assessed by one investigator. The diagnosis of BPH and prostate cancer was established from histological findings. RESULTS: The mean (sd) RI in the transition zone was significantly higher only in patients with BPH, at 0.77 (0.05), vs 0.65 (0.05) in the other two groups. In the peripheral and central zones there was no significant difference in the RI among the three groups. Arterial CDUS flow velocity was increased in the transition zone of patients with BPH, but not in the peripheral and central zones. CONCLUSIONS: The present results support the hypothesis that an age-related impairment of blood supply to the lower urinary tract might have a role in the development of BPH. Although prostate cancer cannot be excluded by measuring RI, high RI values (>0.75) in the transition zone are indicative of BPH.

Adult↗

PubMed2006

The expression of transcription factor activating transcription factor 3 in the human prostate and its regulation by androgen in prostate cancer.

PURPOSE: ATF3 is a member of the basic leucine zipper/cyclic adenosine monophosphate responsive element binding protein family of transcription factors. There is overwhelming evidence that it is a stress inducible factor acting in a signal-type and cell-type dependent manner, and it is involved in cell proliferation and survival. We found that ATF3 was differently expressed in an in vitro prostate cancer tumor progression model and we investigated the possible role of ATF3 in prostate cancer. MATERIALS AND METHODS: ATF3 up-regulation in vivo/in vitro and androgen regulation were assessed by immunohistochemistry and immunoblot analysis. Results after forced ATF3 transfection were evaluated by proliferation assay and cell cycle analysis. RESULTS: Immunohistochemistry and immunoblot analysis revealed ATF3 up-regulation in prostate cancer in vitro and in vivo, and stimulation of expression by androgens. Antiandrogen treatment decreased ATF3 expression in androgen sensitive cells but acted as a stimulator in long-term androgen ablated cells representing a model for therapy refractory disease. Expression in tumors increased with higher Gleason scores and highest expression was observed in samples of therapy refractory tumor tissue. Forced ATF3 over expression in a prostate cancer cell line induced cell proliferation and accelerated cell cycle progression from G1 to S-phase. CONCLUSIONS: These data provide new insight into the role of ATF3 in prostate cancer development and/or progression. They indicate that ATF3 is an androgen regulated gene that is highly expressed in prostate tumors and stimulating cell proliferation. It represents a possible target for prostate cancer therapy.

Activating Transcription Factor 3↗

PubMed2005

Small G-protein RhoE is underexpressed in prostate cancer and induces cell cycle arrest and apoptosis.

BACKGROUND: RhoE/Rnd3, a recently described novel member of the Rho GTPases family, was discussed as a possible antagonist of the RhoA protein that stimulates cell cycle progression and is overexpressed and/or overactivated in prostate cancer. We investigated the expression of RhoE and its role in cell cycle regulation and apoptosis in the human prostate. METHODS: RhoE expression in cell lines and tissue specimens was assessed by immunoblot analysis, real-time PCR (RT-PCR), and immunohistochemistry. To elucidate RhoE effects on the prostate, RhoE was cloned and overexpressed in DU-145 prostate cancer. Cell cycle modulation and apoptosis was investigated by immunoblot and FACS analysis. RESULTS: Immunoblot analysis showed a strong RhoE signal in both, benign epithelial and stromal cells. In contrast, almost no protein was detected in various prostate cancer cells. On RT-PCR and microarray analysis, RhoE mRNA expression was significantly reduced in malignant tissue when compared to benign samples. RhoE immunostaining was strong in benign tissue, especially in prostate epithelial cells, whereas it was minimal or absent in malignant tissue. Forced RhoE overexpression in a prostate cancer cell line inhibits the expression of two proteins essential for G2/M transition, namely CDC2 and cyclin B1, and induces G2/M arrest. In addition, apoptotic cell death as measured by a cleavage product of caspase 3 is significantly increased in RhoE-overexpressing cells. CONCLUSION: In conclusion, our findings suggest RhoE as a tumor suppressor gene that is downregulated early in the development of prostate cancer.

Apoptosis↗

PubMed2005

Are transition zone biopsies still necessary to improve prostate cancer detection? Results from the tyrol screening project.

OBJECTIVES: The present retrospective study was designed to investigate the value of transition zone (TZ) biopsies for prostate cancer (PC) detection rate in a combined contrast enhanced color Doppler targeted (CECD) and gray-scale systematic biopsy (SB) approach. METHODS: PSA screening participants totalling 1475 with tPSA of >1.25 ng/ml (fPSA< or =18%) were assessed. Ten SB and additionally 5 or fewer CECD were performed. The impact of TZ biopsies on the PC detection rate and the biological significance of the detected TZ-cancers were analyzed. RESULTS: Out of 1475 biopsied patients, 395 (26.8%) were identified as PC patients; 5925 biopsy cores from these patients were analyzed. In 86 patients (21.8% of PC), we found 102 PC- positive cores in the TZ, and only in 9 of them solitary TZ-cancers without any other PC-location (2.3% of PC or 0.6% of all investigated patients). Pathologic findings after retropubic prostatectomy (RPE) revealed multifocal adenocarcinoma including involved peripheral zone (PZ) in eight of these nine patients, and solitary TZ-cancer in one patient. There was no positive correlation between prostate volume and TZ-detection rate and no patient with solitary TZ-PC after rebiopsy. CONCLUSION: Biopsy revealed 9 solitary TZ cancers (1.8%) and RPE revealed only one of them to be truly TZ-confined cancer (0.6%). Furthermore PC-detection did not improve, even in patients with rebiopsy, and there was no correlation between detection of TZ-cancers and prostate volume. A combined use of CECD and SB to investigate participants of a PSA-screening program suggests that TZ-biopsies do not improve PC detection rate and are therefore unnecessary.

Adult↗

PubMed2005

Longitudinal PSA changes in men with and without prostate cancer: assessment of prostate cancer risk.

BACKGROUND: To determine longitudinal PSA changes over a period of 10 years in patients with and without prostate cancer. METHODS: Serial PSA measurements performed over 10 years were evaluated in 353 men who eventually developed prostate cancer and in 2.462 participants of a screening program without prostatic malignancy. RESULTS: In men with cancer, mean tPSA increased from 2.28 ng/ml at 10 years before diagnosis to 6.37 ng/ml at the time of postive biopsy (PSA velocity: 0.409 ng/ml/year). PSA velocity was significantly associated with Gleason scores and pathologic stage. In the benign group (n=2.462), mean tPSA increased from 1.18 to 1.49 ng/ml over a period of 10 years (PSA velocity of 0.03 ng/ml/year). Of the subjects with tPSA levels of 2 ng/ml or less, 2 years prior to cancer diagnosis, 11.4% had tPSA values of more than 4 ng/ml at the time of biopsy. Of the 972 men with tPSA below 1 ng/ml 2 years before the most recent measurement was obtained, 966 (99.4%) had no evidence of prostate cancer 2 years later, while six were found to have malignancies (0.6%). CONCLUSIONS: Longitudinal PSA changes in men with and without prostate cancer are significantly different. Annual testing may not be required in men with baseline tPSA levels of 1 ng/ml or below, whereas in patients with levels higher than 1 ng/ml, it seems to be indicated because of the significant percentage of men presenting with tPSA levels of more than 4 ng/ml two years later.

Adult↗

PubMed2005

Androgen receptor down regulation by small interference RNA induces cell growth inhibition in androgen sensitive as well as in androgen independent prostate cancer cells.

We investigated the effects of androgen receptor (AR) down regulation with a small interference RNA molecule (siRNA_AR(start)) on androgen sensitive LNCaP and androgen independent LNCaPabl prostate cancer cells, the latter representing an in vitro model for the development of therapy resistance in prostate cancer. Although LNCaPabl cells express increased levels of AR in comparison with androgen sensitive LNCaP cells, the protein was significantly down regulated in response to siRNA_AR(start) treatment. This AR down regulation resulted in a marked cell growth inhibition in both cell lines. By contrast, DU-145 prostate cancer cells, which lack AR expression, were not inhibited by the siRNA_AR(start). In consequence to AR down regulation, both cell lines, LNCaP and LNCaPabl, shared a highly similar gene expression profile in terms of major changes in cell cycle regulatory genes. The cell cycle inhibitor p21(Waf1/Cip1) as well as cyclin D1 were significantly up regulated by siRNA_AR(start) treatment, considering a switch in cyclin expression towards cell cycle retardation. Control molecules had moderate effects on cell proliferation and gene expression, respectively. In summary, we found that AR inhibition with siRNA induces cell growth retardation in androgen sensitive as well as in androgen independent prostate cancer cells and thus may represent an interesting approach to combat hormone-refractory prostate cancer.

Androgen Receptor Antagonists↗

PubMed2005

Detection rates and biologic significance of prostate cancer with PSA less than 4.0 ng/mL: observation and clinical implications from Tyrol screening project.

OBJECTIVES: To investigate the prostate cancer (PCa) detection rates and Gleason scores in patients with serum prostate-specific antigen (PSA) levels of 2.0 to 3.9 ng/mL and 4.0 to 10 ng/mL (free PSA 18% or less), in a population-based screening project. With the use of prostate-specific antigen (PSA) screening, more PCa is being diagnosed at PSA values of less than 4 ng/mL. METHODS: A total of 3446 consecutive screening volunteers with a PSA level of 2.0 to 10.0 ng/mL (free PSA 18% or less) were assessed. Ten systematic prostate biopsies and an additional five Doppler-enhanced targeted biopsies were performed on the basis of age-specific PSA reference ranges. The cumulative frequency of detection and the Gleason scores were analyzed. RESULTS: The PCa detection rate for patients with a PSA value of 2.0 to 3.9 ng/mL (n = 1522, group 1) and 4.0 to 10.0 ng/mL (n = 1924, group 2) was 21% (n = 320) and 30% (n = 572), respectively. Of the PCa cases detected, 37% were in men with a PSA level of 2 to 4 ng/mL. Statistically significant differences were found in age and prostate volume between groups 1 and 2, with patients in the lower PSA group younger and having a smaller mean prostate volume (P = 0.0001). Of 313 patients with PCa and a PSA value of 2 to 3.9 ng/mL, 24% had a Gleason score of 7 or greater compared with 33% of 560 patients with a PSA value of 4.0 to 10.0 ng/mL (P = 0.004). CONCLUSIONS: Our data suggest that in a screening population, more than one third of PCa cases in men with a PSA level of 2 to 10 ng/mL will occur in those with a PSA value of 2 to 3.9 ng/mL. Also, PCa cases with a low PSA level occur in younger patients and at lower stages with a smaller prostate volume.

Adult↗

PubMed2005

Prostate cancer detection in men with prostate specific antigen 4 to 10 ng/ml using a combined approach of contrast enhanced color Doppler targeted and systematic biopsy.

PURPOSE: Transrectal gray scale ultrasound guided biopsy is the standard method for diagnosing prostate cancer (PC). Improved cancer detection with ultrasound contrast agents is related to better detection of tumor vascularity. We evaluated the impact of a combined approach of contrast enhanced, color Doppler targeted biopsy (CECD) and systematic biopsy (SB) for the PC detection rate in men with prostate specific antigen (PSA) 4.0 to 10 ng/ml. MATERIALS AND METHODS: We examined 380 screening volunteers with a total PSA of 4.0 to 10 ng/ml (percent free PSA less than 18). CECD was always performed before SB. Another investigator blinded to contrast enhanced findings performed 10 SBs. The cancer detection rate for the CECD, SB and combined approaches was assessed. RESULTS: PC was detected in 143 of 380 patients (37.6%, mean total PSA 6.2 ng/ml). The PC detection rate for CECD and for SB was 27.4% and 27.6%, respectively. The overall cancer detection rate with the 2 methods combined was 37.6%. For targeted biopsy cores the detection rate was significantly better than for SB cores (32.6% vs 17.9%, p <0.01). CECD in a patient with cancer was 3.1-fold more likely to detect PC than SB. CONCLUSIONS: CECD allows for the detection of lesions that cannot be found on gray scale ultrasound or SB. CECD allows for assessment of neovascularity associated with PC. However, the combined use of CECD and SB allows for maximal detection of PC with a detection rate of 37.6% in our patients with PSA 4 to 10 ng/ml.

Adult↗

PubMed2005

Vascular damage as a risk factor for benign prostatic hyperplasia and erectile dysfunction.

OBJECTIVE: To assess benign prostatic hyperplasia (BPH) and erectile dysfunction (ED), both considered to be associated with urogenital ageing, in ageing men in a cross-sectional population study, comparing them with healthy controls by using symptom scores and contrast-enhanced colour Doppler ultrasonography (CDUS). PATIENTS, SUBJECTS AND METHODS: Transrectal CDUS and quantitative measurement of colour pixel intensity (CPI) are excellent minimally invasive techniques for assessing normal and pathological blood flow. CDUS was performed using the microbubble-based ultrasound enhancer for evaluating prostate, bladder neck and corpus cavernosum vascularity in young healthy men, men with BPH, and men with severe vascular damage (diabetes mellitus type 2). Resistive index measurements and computer-assisted quantification of CPI were used to objectively evaluate perfusion. The International Prostate Symptom Score (IPSS) and the International Index of Erectile Function (IIEF) were applied to quantify the symptoms. RESULTS: In patients with BPH, perfusion of the transition zone (TZ) of the prostate was significantly lower and the resistive index of the TZ significantly higher (both P < 0.001) than in healthy controls. The perfusion patterns of men with BPH and those who also had severe vascular damage (diabetes mellitus type 2) showed that vascularity in the latter group was lower in the prostatic TZ and the corpora cavernosa. In patients with BPH the IPSS, quality-of-life and IIEF scores were significantly worse than in the control group. Men with concomitant atherosclerosis had even worse symptom scores. CONCLUSION: These results strongly support the hypothesis that age-related impairment of blood supply to the lower urinary tract is important in the development of BPH and ED. Vascular damage may cause chronic ischaemia and thus be a contributing factor in the pathogenesis of BPH and ED.

Adult↗

PubMed2005

The effect of percentage free prostate-specific antigen (PSA) level on the prostate cancer detection rate in a screening population with low PSA levels.

OBJECTIVE: To evaluate the prostate cancer detection rate at low total prostate-specific antigen (tPSA) ranges of 2.6-4 and 4.1-10 ng/mL, according to different percentage free (f/t) PSA levels in a screening population. SUBJECTS AND METHODS: In all, 1809 consecutive screening volunteers with a tPSA level of 2.6-10.0 ng/mL were assessed. Ten systematic ultrasonography-guided prostate biopsies and, since 2000, an additional five Doppler-enhanced targeted biopsies were taken on the basis of age-specific tPSA reference ranges. We analysed the detection rate of prostate cancer according to f/tPSA ranges of 0-9%, 10-14%, 15-18% and >18%. RESULTS: The detection rates for the subgroups with tPSA levels of 2.6-4.0 and 4.1-10.0 ng/mL were 20.2% and 27.0%, respectively. The cancer detection rate in the first group (2.6-4.0 ng/mL) at 0-10% fPSA was 22.9%, and that in the second group (4.1-10.0 ng/mL) at 0-10% was 36.9%. There were significant differences between these groups. If the f/tPSA was 10-15%, the cancer detection rate for the two groups were 22.6% and 32.5%, respectively (P < 0.05). There was no statistically significant difference in the cancer detecting rates at an f/tPSA of 15-18% or >18%. CONCLUSION: There is a statistically significantly higher cancer detection rate when the f/tPSA is <15% than in groups of men with a f/tPSA of >15% in screening population assessed primarily using tPSA level.

Adult↗

PubMed2005

Molecular effects of the isoflavonoid genistein in prostate cancer.

Differences in diet have been proposed to be at least partially responsible for the low rate of prostate cancer in Asian populations compared with men in Western countries. One of the compounds that occurs in a greater quantity in the Eastern diet is genistein, an isoflavonoid found in high concentrations in serum after ingestion of soy-rich foods. Extensive molecular studies have been performed to determine its potential health benefits. The mechanism of action of genistein is complex and includes several cellular pathways. In addition to its estrogenic and/or antiestrogenic activities, genistein has been reported to inhibit steroidogenesis and block several protein tyrosine kinases, including epidermal growth factor receptor and src tyrosine kinases. Moreover, it arrests the cell cycle, induces apoptosis, and has antiangiogenic and antimetastatic properties and antioxidant activity. Herein, we review the current literature on the molecular mechanisms of genistein in relation to its effects on prostate cancer cells.

Animals↗

PubMed2004

Androgen receptor regulation by physiological concentrations of the isoflavonoid genistein in androgen-dependent LNCaP cells is mediated by estrogen receptor beta.

OBJECTIVES: Isoflavonoids are discussed for use in chemoprevention and treatment of prostate cancer. We investigated the potential of genistein to modulate androgen receptor (AR) expression and transcriptional activity in the human androgen-sensitive prostate cancer cell line LNCaP. MATERIALS AND METHODS: AR expression at mRNA and protein level was analyzed by real-time RT-PCR and immunoblot, respectively. In conditioned media PSA was measured by a microparticle enzyme immunoassay (MEIA). Binding of genistein to the AR was tested in a radioligand-binding assay and reporter gene co-transfection assay was employed to investigate AR activity. RESULTS: Using concentrations of genistein that have been detected in sera of Asian men on regular soy-diet we found down-regulation of androgen receptor at both mRNA and protein level. The relative binding affinity to the AR was below 4% when compared to methyltrienologe (R1881) and there was no modulation of AR transcriptional activity by genistein concentrations up to 1 microM. We also demonstrated inhibition of PSA secretion after genistein treatment. As the anti-estrogen ICI 164 384 abolished the inhibitory effect of genistein and ER-beta, but not ER-alpha is expressed in LNCaP cells we postulate that the mechanism of genistein action on androgen receptor is mediated through ER-beta. CONCLUSION: Using physiological concentrations of genistein we showed AR down-regulation by genistein in prostate cancer cells occurring via ER-beta. This likely results in a modified response to hormonal stimuli and may help to explain the low incidence of prostate cancer in the Asian population.

Antineoplastic Agents↗

PubMed2004

Identification of genes involved in estrogenic action in the human prostate using microarray analysis.

Estrogens have profound effects on the developing prostate and are suspected to contribute to the development of benign prostatic hyperplasia, but the mechanism by which this hormone elicits its regulatory function still remains largely unknown. Using complementary RNA microarrays comprising approximately 10,000 oligonucleotide gene targets we compared differences in mRNA expression of estradiol-treated and untreated prostatic stromal cells in vitro. Based on a threshold of greater than twofold change, 228, 241, and 464 of the expressed genes were found to be regulated by estradiol after 10, 24, and 48 h of treatment, respectively. The secondary analysis of one estradiol-activated transcript, namely lipopolysaccharide-binding protein, and four estradiol-repressed genes, namely ras homolog gene family member E (RhoE/Rnd3), ubiquitin thiolesterase, interleukin 6, and interleukin 8 (IL-8), by real-time quantitative PCR confirmed the results of the microarray analysis. Moreover, IL-8 and RhoE were found to be down-regulated by estradiol at the protein level as well. We identified a set of genes involved in a wide range of cellular functions that are potentially important for understanding the molecular basis of estradiol action in the prostate.

Acute-Phase Proteins↗

PubMed2004

Safer transurethral resection of the prostate: coagulating intermittent cutting reduces hemostatic complications.

PURPOSE: Transurethral resection of the prostate (TURP) is still the gold standard for the surgical treatment of symptomatic benign prostatic hyperplasia. However, the associated morbidity and blood loss remain concerns. A coagulating intermittent cutting (CIC) device with constant voltage pulses and controlled pulse intervals was recently developed. The impact of CIC on bleeding and blood transfusion rates as well as the occurrence of the TUR syndrome were investigated. MATERIALS AND METHODS: From January 2000 to July 2002, 271 consecutive patients with symptomatic benign prostatic hyperplasia underwent TURP with the CIC device. In addition to blood transfusion rates, serum hemoglobin and electrolytes were determined in all patients immediately before and after TURP. RESULTS: The mortality rate in the 271 patients subjected to TURP was 0.0%. Mean decrease in hemoglobin after TURP was 1.08 mg/dl. Intraoperative and postoperative blood transfusions were required in 7 patients (2.6%), and clinical signs of the transurethral resection syndrome were noted in 1.1% of patients. CONCLUSIONS: Coagulating intermittent cutting dramatically improves the safety of TURP by decreasing intraoperative and postoperative blood loss, and the rate of blood transfusions. With this blood sparing device we anticipate a lower incidence of hemostatic complications from TURP.

Adult↗

PubMed2004

Phytoestrogens derived from Belamcanda chinensis have an antiproliferative effect on prostate cancer cells in vitro.

PURPOSE: Phytoestrogens are nonsteroidal plant derived compounds with estrogenic activity that have been implicated in protecting against prostate cancer progression. We hypothesized that these compounds would alter cell number and increase the ability of antiandrogens to induce cell death in prostate cancer cells. MATERIALS AND METHODS: RWPE-1, LNCaP and PC-3 cells were treated with or without an extract of Belamcanda chinensis, 2 purified phytoestrogens derived from this extract (irigenin and tectorigenin) and the antiandrogen bicalutamide. We assessed the effect on cell number, proliferation and apoptosis. RESULTS: Phytoestrogens (50 to 100 microM) and bicalutamide (10 to 50 microM) alone decreased the cell number in all 3 cell lines. Phytoestrogens (50 microM) combined with bicalutamide (10 microM) further decreased the number of RWPE-1 and PC-3 cells compared to these agents alone. Tectorigenin and irigenin inhibited the proliferation of RWPE-1, LNCaP and PC-3 cells, causing G1 arrest and the induction of p21WAF1 or p27 protein expression, whereas bicalutamide induced apoptosis in a dose dependent manner in all 3 cell lines. Phytoestrogens did not have antiandrogenic activity. CONCLUSIONS: These in vitro studies demonstrate a role for tectorigenin and irigenin in regulating prostate cancer cell number by inhibiting proliferation through cell cycle regulation.

Cell Division↗

PubMed2003

Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia.

BACKGROUND: Local hypoxia may be one of the triggers of embryonic reawakening of the stroma and subsequent hyperplastic growth in the prostate. Using a cell culture model of human prostatic stromal cells, we investigated the effects of hypoxia on activation of hypoxia-inducible factor 1 (HIF 1) and on the production of growth factors. METHODS: Primary prostatic stromal cells were grown in normal and hypoxic (1% O(2)) atmosphere. Activation of HIF 1 was evaluated after different time intervals by Western blot. Induced secretion of growth factors VEGF, FGF-7, TGF-beta, IL 8, and FGF-2 were analyzed by ELISA. To confirm the in vitro findings we also performed immunohistochemistry of HIF 1alpha as well as pro-collagen I, collagens I, III, and IV in the benign tissue of radical prostatectomy specimens. RESULTS: HIF 1 is activated in a time-dependent manner, already starting 1 hr after exposure of stromal cells to hypoxic conditions. Secretion of VEGF, FGF-7, TGF-beta, FGF-2, and IL 8 is increased under hypoxic in vitro conditions in comparison to normoxia. Levels of TGF-beta, VEGF, and IL 8 were rapidly and statistically significantly increased in the supernatant of hypoxic cells. Consistent with the in vitro findings, immunohistochemistry of HIF 1alpha in (benign prostatic hyperplasia) BPH tissue revealed strong HIF 1alpha nuclear staining in hyperplastic areas. No difference was observed in the collagen pattern between hyperplastic and normal prostate tissue. CONCLUSIONS: Prostatic stromal cells respond to hypoxia by upregulation of secretion of several growth factors suggesting that hypoxia can trigger prostatic growth. Therefore, hypoxia might be a key factor contributing to the pathogenesis of BPH.

Cell Line↗