[Show abstract][Hide abstract] ABSTRACT: Prostate cancer (PCa), the most commonly diagnosed cancer and second leading cause of male cancer death in Western societies, is typically androgen-dependent, a characteristic that underlies the rationale of androgen deprivation therapy (ADT). Approximately 90% of patients initially respond to ADT strategies, however many experience side effects including hot flashes, cardiotoxicity, metabolic and musculoskeletal alterations. This review summarizes pre-clinical and clinical studies investigating the ability of dietary supplements to alleviate adverse effects arising from ADT. In particular, we focus on herbal compounds, phytoestrogens, selenium (Se), fatty acids (FA), calcium, and Vitamins D and E. Indeed, there is some evidence that calcium and Vitamin D can prevent the development of osteoporosis during ADT. On the other hand, caution should be taken with the antioxidants Se and Vitamin E until the basis underlying their respective association with type 2 diabetes mellitus and PCa tumor development has been clarified. However, many other promising supplements have not yet been subjected large-scale clinical trials making it difficult to assess their efficacy. Given the demographic trend of increased PCa diagnoses and dependence on ADT as a major therapeutic strategy, further studies are required to objectively evaluate these supplements as adjuvant for PCa patients receiving ADT.
[Show abstract][Hide abstract] ABSTRACT: This study aimed to investigate the mechanisms underlying the anti-proliferative effects of the ethanolic Cimicifuga racemosa extract BNO-1055 on prostate cells and evaluate its therapeutic potential. BNO-1055 dose-dependently attenuated cellular uptake and incorporation of thymidine and BrdU and significantly inhibited cell growth after long-time exposure. Similar results were obtained using saponin-enriched sub-fractions of BNO-1055. These inhibitory effects of BNO-1055 could be mimicked using pharmacological inhibitors and isoform-specific siRNAs targeting the equilibrative nucleoside transporters ENT1 and ENT2. Moreover, BNO-1055 attenuated the uptake of clinically relevant nucleoside analogs, e.g. the anti-cancer drugs gemcitabine and fludarabine. Consistent with inhibition of the salvage nucleoside uptake pathway BNO-1055 potentiated the cytotoxicity of the de novo nucleotide synthesis inhibitor 5-FU without significantly altering its uptake. Collectively, these data show for the first time that the anti-proliferative effects of BNO-1055 result from hindered nucleoside uptake due to impaired ENT activity and demonstrate the potential therapeutic use of BNO-1055 for modulation of nucleoside transport.
Phytomedicine: international journal of phytotherapy and phytopharmacology 08/2013; · 2.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:The TMPRSS2-ERG gene fusion resulting in ERG overexpression has been found in around 50% of prostate cancers (PCa) and is a very early event in tumorigenesis. Most studies have reported on selected surgical cohorts with inconsistent results. We hypothesized that ERG gene rearrangements impact tumor development and investigated the frequency of ERG overexpression in the context of clinicopathological tumor characteristics.METHODS:ERG overexpression (ERG+ or ERG-) was determined by immunohistochemistry (IHC) in 1039 radical prostatectomy (RP) tumors and association with PSA, D'Amico risk score, histopathology, biochemical recurrence, body mass index and age of PCa cases was analyzed.RESULTS:ERG+ was associated with younger age at diagnosis (P<0.0001), lower serum PSA (P=0.002) and lower prostate volume (PV) (P=0.001). It was most frequent in the youngest age quartile (55 years, 63.9% ERG+) and decreased constantly with increasing age to 40.8% in the oldest age quartile (67 years, P<0.0001). In the PSA range <4 ng ml(-1) the frequency of ERG positivity was 60.2% compared with 47.5 and 49.1% in the PSA ranges 4-10 and 10 ng ml(-1), respectively. In the first age quartile, ERG+ patients had lower median serum PSA and fPSA% and smaller PV. In the highest age quartile tumor volume (TV) was increased. Similar differences were observed in the low PSA range. Multivariate analysis identified the first age quartile as a predictor for ERG status (odds ratios (OR) 2.05, P=0.007). No association was found with the D'Amico progression risk score and with biochemical tumor recurrence.CONCLUSIONS:ERG+ tumors manifest clinically at lower PSA levels and their prevalence is age dependent. This suggests acceleration of tumor development by ERG overexpression that results in earlier tumor detection in young patients. Long-term results are warranted to determine the impact of ERG overexpression on disease outcome.Prostate Cancer and Prostatic Disease advance online publication, 5 February 2013; doi:10.1038/pcan.2013.4.
Prostate cancer and prostatic diseases 02/2013; · 2.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Various findings implicate sex hormones in prostate growth and development and also in prostate carcinogenesis. We investigated if addition of sex steroid hormone and sex hormone binding globulin (SHBG) serum levels to standard risk assessment parameters [prostate-specific antigen (PSA), free PSA percentage (fPSA%), and age] improves prostate cancer prediction in a PSA screening setting. Steroid hormones testosterone (T), free testosterone (fT), and estradiol (E2), and binding protein SHBG levels were measured in 762 men undergoing prostate biopsy due to suspect PSA serum levels. Prostate cancer was diagnosed in 286 (37.5%) of these men. Our data confirmed that PSA (mean BE=5.09; mean CA=6.05; p=1.24×10–5), fPSA% (mean BE=22.08; mean CA=18.67; p=1.97×10–7), and age (mean BE=60.64; mean CA=64.5; p=7.05×10–10) differentiate men with cancer (CA) and men with benign disease (BE), such as benign prostate hyperplasia. In addition, SHBG (mean BE=50.3; mean CA=54.9; p=0.008) also differed statistically significantly between these two groups. All hormones except E2 and tumor markers correlated significantly with age (T: ρ=–0.09; fT: ρ=–0.27; SHBG: ρ=0.21; PSA: ρ=0.32; and fPSA%: ρ=0.22). Furthermore, we found that PSA correlates with E2 (ρ=0.08), and fPSA% with SHBG (ρ=0.1) and fT (ρ=–0.09). Addition of hormones and SHBG to a baseline marker model including PSA, fPSA%, and age improved cancer prediction in three multivariate classification methods; however, the improvement was minimal. The best improvement by 0.8% was obtained in the logistic regression model with the addition of T and SHBG or of E2 and SHBG, or in the support vector machine model with the addition of SHBG and all steroid hormones to the combination of standard markers PSA, fPSA%, and age; however, this additional gain of accuracy is too small to justify the additional efforts and costs.
Hormone molecular biology and clinical investigation 06/2012;
[Show abstract][Hide abstract] ABSTRACT: Patients with metastatic renal cell carcinoma (RCC) undergoing cytokine or targeted therapies may show a remarkable decline in quality of life (QoL). We wanted to evaluate QoL in patients with metastatic RCC undergoing therapeutic vaccination with dendritic cells (DCs). In a cross-sectional analysis, QoL was therefore assessed in RCC patients participating in three consecutive clinical trials of DC vaccination. Before the first and after the third vaccination with DCs, patients completed a QoL questionnaire (EORTC QLQ-C30, version 3). Data were transformed into scale scores and analysed using SPSS 12.0 software. Mean values of the resulting scores obtained before and after DC vaccination were compared using students t test and Wilcoxon rank-sum test. P < 0.05 was considered statistically significant. The questionnaire was completed by 55 of 71 patients (compliance rate, 77.5%) who had a median age of 58.7 years (from 30 to 75 years). No significant reductions in functioning scales including physical, emotional and social criteria as well as symptom scores, which assess typical symptoms of tumour therapies, were observed indicating that QoL remained high during DC vaccination. Significant correlations were found between overall survival and functional as well as symptom scores. Our data indicate that DC vaccination, which is a personalised treatment modality, maintains QoL and thus represents an attractive nontoxic treatment option for patients with metastatic RCC. It will be important to identify the most effective conditions of DC vaccination including combinations with other therapeutics to maximise clinical efficacy while still preserving QoL.
Cancer Immunology and Immunotherapy 01/2012; 61(9):1407-13. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To report an observed high frequency of Leydig cell tumours (LCTs) diagnosed at our centre.
Charts of all patients who underwent surgery for a testicular tumour between 1999 and 2008 at our department were searched and data from patients with LCT were collected. Before surgery all patients underwent ultrasound and complete staging. In all but two patients with LCT an organ-sparing surgery was performed. Surgery was performed under ultrasound or palpation guidance. All patients underwent postoperative follow-up. We retrospectively reviewed surgical technique, histology, epidemiology and outcome in all LCT patients.
In the study period, 197 testicular tumours were surgically removed of which 29 were diagnosed as LCT (14.7% of 197; further study group) in 25 patients. Mean age of patients with LCT was 45 years (range 21-68 years). Tumour size ranged from 1.2 to 80 mm (mean 10.23 mm). In two patients (8%) the lesion was palpable whereas incidental diagnosis was made in seven patients (28%). In the remaining patients diagnosis was made by ultrasound performed for testicular pain (six patients, 24%) or during infertility or erectile dysfunction evaluation (10 patients, 40%). Definitive histology reported no malignant histopathological features in all but one patient; this particular patient experienced tumour progression after 2 months and died from advanced disease 1 year later. All other patients are free of disease after a mean follow up of 56 months (range 7-93 months). During this period one patient developed a second LCT on the contralateral side; another patient had a recurrence within the same testicle, but on the opposite pole. Both underwent a subsequent organ-sparing tumour resection.
The percentage of LCT (14.7% of all testicular tumours removed) was significantly higher than expected from the literature. One possible explanation for this phenomenon is the increasing use of better ultrasound technology and the subsequent increased detection of small nodules that have not been found in historical series. Use of 'observation-only' for very small lesions detected at infertility clinics is under debate.
BJU International 06/2011; 108(10):1603-7. · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: • To elucidate the association of progression of advanced renal cell carcinoma with anaemia and investigate factors influencing tumor-associated anaemia.
• We analyzed different clinical variables to study associations with anaemia in 86 metastatic renal cell carcinoma patients. • 45 (52%) of patients had already developed anaemia prior to therapy.
• Anaemic patients had an increase in the serum markers C-reactive protein (CRP), IL-6 and erythropoietin (EPO). In addition we observed substantial correlation between IL-6 and CRP serum levels (R = 0.639, P < 0.0001). • Univariate logistic regression analysis revealed that patients with IL-6 >10 pg/mL had a considerable increase in risk for anaemia (odds ratio 3.86, P= 0.003). • In addition, patients with CRP >0.7 mg/dL had a very strong increase in risk for anaemia (OR = 14.08, P < 0.0001). • Stepwise multivariate logistic regression analysis confirmed CRP >0.7 mg/mL as the only independent predictor for anaemia. Cox-regression modeling selected serum IL-6 as the strongest independent prognostic indicator (hazard ratio 3.58, P < 0.0001).
• Anaemia depends on serum IL-6, which is a strong inductor of CRP and regulator of the iron-transport. Serum IL-6 may be considered as a target to treat cancer-related anaemia.
BJU International 11/2010; 107(12):1893-8. · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In contrast to hematologic malignancies, little is known about the role of fungi in the development and progression of solid tumors. This prompted us to analyze and correlate serum levels of different fungal IgG with survival of patients with metastatic renal cell carcinoma.
Serum IgG to Candida sp., Saccharomyces cerevisiae and Aspergillus fumigatus were measured in a cross-sectional study in 64 patients with advanced disease. Univariate and multivariate analyses were chosen to study serum IgG as prognostic indicators.
Median follow-up was 29.0 months (range 0.3-122). Median overall survival of patients, which tested negative for Candida IgG, was significantly increased (median not reached, >29 months) compared with Candida IgG positive patients (17.8 months, P = 0.002). Median survival of Saccharomyces IgG negative patients was 33.1 months as opposed to 19.4 months in Saccharomyces IgG positive patients, although this difference was not significant (P = 0.281). No difference in overall survival was found between Aspergillus IgG positive patients (28.0 months) and Aspergillus IgG negative patients (29.1 months) (P = 0.181). Cox backward-stepwise regression confirmed Candida IgG as the strongest predictor of survival in metastatic renal cell carcinoma patients (risk ratio 3.27, P = 0.001, [95% CI 1.86-5.73]).
Our findings suggest that IgG antibodies directed against yeast fungi and particularly against Candida but not against mold fungi have prognostic relevance.
Cancer Immunology and Immunotherapy 02/2010; 59(8):1141-7. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction: We retrospectively analysed the predictive value of numerous clinical and radiological parameters to identify a predictor for either necrosis or residual tumors found by retroperitoneal lymph node dissection (RPLND) histology in a collection of nonseminomatous germ cell tumor (NSGCT) patients. Materials and Methods: A database was created containing detailed clinical, radiological and histological information of all consecutive NSGCT patients, who underwent post chemotherapy RPLND between 1984 and 2007. According to the histology of the RPLND specimen, patients were assigned to the “necrosis-only” group or the “residual tumor” group. Associations between clinical and radiological parameters and histology of RPLND were analyzed. Results: Histology of dissected masses showed complete necrosis in 57.4% of patients and residual tumors in 42.6% (3.1% viable cancer and 39.5% teratoma). Univariate analysis showed significant correlation of RPLND histology and the following parameters: teratoma-positive primary tumors, pre-chemotherapy α-fetoprotein (AFP) and – less pronounced – human chorionic gonadotropin levels, size of metastatic mass, total volume of metastatic retroperitoneal lymph nodes, and percentage of volume reduction. The best prediction for necrosis in RPLND histology was in patients with no evidence of teratomatous elements in primary tumors and with normal pre-chemotherapy AFP levels and small lymph nodes. Stepwise multivariate logistic regression analysis confirmed AFP < 10 ng/ml as the best independent predictor for only necrosis in RPLND histology. Conclusions: At the present time we still consider all patients with metastatic NSGCT as candidates for a post-chemotherapy RPLND, arguing that in experienced hands mortality is negligible and morbidity is low and therefore not relevant compared to the risk of missing a residual tumor.
[Show abstract][Hide abstract] ABSTRACT: A recent study reported that a diet rich in bread and refined cereals might have an unfavorable role in the development of renal cell carcinoma (RCC). To test whether an underlying intolerance of bread ingredients is responsible for the unfavorable influence of bread on RCC, we examined patient sera for the presence of food-specific IgG.
A commercial test was used to detect food-specific IgG directed against a panel of 113 food antigens in sera of 54 patients with metastatic RCC. Kaplan-Meier estimates were used for univariate survival analysis, and differences in survival curves were assessed with the log-rank test. Multivariate survival analysis was done using a Cox regression model.
We found that RCC patients with elevated serum levels of IgG antibodies against S. cerevisiae, commonly known as baker's yeast and yet another bread component, have an unfavorable clinical course. Median survival of patients with high levels of S. cerevisiae IgG was only 17.8 months, whereas median survival of patients with low S. cerevisiae IgG was 43.8 months (P = 0.0022; log-rank). Multivariate survival analysis identified high levels of S. cerevisiae IgG as a strong and independent prognostic risk factor (risk ratio 4.6, P = 0.001; 95% CI 1.61-13.08).
Our findings indicate that serum levels of IgG against S. cerevisiae may predict survival in patients with metastatic RCC. The data suggest not cereals but baker's yeast being the critical component of bread that may cause immune deviation and impaired immunosurveillance in predisposed RCC patients.
Cancer Immunology and Immunotherapy 09/2008; 57(8):1207-14. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the pathological features of Gleason score 6 prostate cancers after radical prostatectomy in the low (<4 ng/mL) and intermediate range of prostate-specific antigen level (4-10 ng/mL), as such prostate cancers are considered to be well differentiated tumours with a low risk for recurrence after therapy.
In all, 1354 patients with T1c prostate cancer and PSA levels of <10.0 ng/mL had a radical retropubic prostatectomy. Patients with Gleason score 6 tumours were divided into two groups, those with PSA levels of <4 and 4.0-10.0 ng/mL. Extracapsular extension, positive surgical margins, biochemical recurrence (BCR) and mean time to BCR were evaluated.
Of the 1354 patients, there were 437 (32.3%) with Gleason score 6 prostate cancers. Patients in the low PSA group had less extraprostatic disease than those with a higher level (5.9% vs 14.5%) and both groups had an almost equal proportion of positive surgical margins (9.4% vs 11.0%). In the low PSA group there was statistically significantly shorter BCR than in the high PSA group, with a mean time to BCR of 1.7 vs 3.1 years.
These results show a statistically significantly higher rate of extraprostatic disease and earlier BCR in men with a high than a low PSA level even in Gleason score 6 prostate cancer. As the rate of BCR and extracapsular extension are significantly related to prostate cancer mortality, these findings further support the concept of screening using low PSA levels.
BJU International 04/2008; 101(7):822-5. · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The ability of cultured, antigen-loaded dendritic cells (DCs) to induce antigen-specific T cell immunity in vivo has previously been demonstrated and confirmed. Immune monitoring naturally focuses on immunity against vaccine antigens and may thus ignore other effects of DC vaccination. Here we therefore focused on antigen-independent responses induced by DC vaccination of renal cell carcinoma patients. In addition to the anticipated response against the vaccine antigen KLH, vaccination with CD83(+) monocyte-derived DCs resulted in a strong increase in the ex vivo proliferative and cytokine responses of PBMCs stimulated with LPS or BCG. In addition, LPS strongly enhanced the KLH-induced proliferative and cytokine response of PBMCs. Moreover, proliferative and cytokine responses of PBMCs stimulated with the homeostatic cytokines IL-7 and IL-15 were also clearly enhanced after DC vaccination. In contrast to LPS induced proliferation, which is well known to depend on monocytes, IL-7 induced proliferation was substantially enhanced after monocyte depletion indicating that monocytes limit IL-7 induced lymphocyte expansion. Our data indicate that DC vaccination leads to an increase in the ex vivo responsiveness of patient PBMCs consistent with a DC vaccination induced enhancement of T cell memory. Our findings also suggest that incorporation of bacterial components and homeostatic cytokines into immunotherapy protocols may be useful in order to enhance the efficacy of DC vaccination and that monocytes may limit DC vaccination induced immunity.
Cancer Immunology and Immunotherapy 07/2007; 56(6):897-903. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bee venom secretory phospholipase A2 (bv-sPLA2) and phosphatidylinositol-(3,4)-bisphosphate (PtdIns(3,4)P2) act synergistically to induce cell death in tumour cells of various origins with concomitant stimulation of the immune system. Here, we investigated the mechanisms involved in such actions and examined structural requirements of PtdIns-homologues to inhibit tumour cells in combination with bv-sPLA2. Renal cancer cells were treated with bv-sPLA2 alone or in combination with PtdIns-homologues. Inhibitory effects on [(3)H] thymidine incorporation and intracellular signal transduction pathways were tested. Reaction products generated by bv-sPLA2 interaction with PtdIns(3,4)P2 were identified by mass spectrometry. Among the tested PtdIns-homologues those with a phosphate esterified to position 3 of the inositol head group, were most efficient in cooperating with bv-sPLA2 to block tumour cell proliferation. Growth inhibition induced by the combined action of bv-sPLA2 with either PtdIns(3,4)bisphosphate or PtdIns(3,4,5)trisphosphate were synergistic and accompanied by potent cell lysis. In contrast, PtdIns, which lacked the phosphate group at position 3, failed to promote synergistic growth inhibition. The combined administration of PtdIns(3,4)P2 and bv-sPLA2 abrogated signal transduction mediated by extracellular signal regulated kinase 1 and 2 and prevented transduction of survival signals mediated by protein kinase B. Surface expression of the epidermal growth factor (EGF)-receptor was reduced after PtdIns(3,4)P2-bv-sPLA2 administration and associated with a blockade of EGF-induced signalling. In addition, mass spectroscopy revealed that bv-sPLA2 cleaves PtdIns(3,4)P2 to generate lyso-PtdIns(3,4)P2. In conclusion, we suggest that the cytotoxic activity mediated by PtdIns(3,4)P2 and bv-sPLA2 is due to cell death that results from disruption of membrane integrity, abrogation of signal transduction and the generation of cytotoxic lyso-PtdIns(3,4)P2.
Cancer Immunology and Immunotherapy 06/2007; 56(5):627-40. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Renal cell carcinoma (RCC) is considered a cytokine-responsive tumor. The clinical course of a patient may thus be influenced by the patient's capacity to produce distinct cytokines. Therefore, cytokine gene polymorphisms in RCC patients were analyzed to determine haplotype combinations with prognostic significance.
A selection of 21 single nucleotide polymorphisms within the promoter regions of 13 cytokine genes were analyzed in a cross-sectional single-center study of 80 metastatic RCC patients. Univariate and multivariate analyses and the Cox forward-stepwise regression model were chosen to assess genetic risk factors.
Multivariate Cox regression analysis confirmed by a bootstrap technique identified the heterozygous IL4 genotype -589T-33T/-589C-33C as an independent prognostic risk factor (risk ratio, 3.1; P < .01; 95% CI, 1.4 to 6.9; adjusted for age, sex, and nuclear grading) in metastatic RCC patients. IL4 haplotype -589T-33T and -589C-33C were found with a frequency of 0.069 and 0.925, respectively, which represents a two-fold decrease of IL4 haplotype -589T-33T (P < .01) and an increase of IL4 haplotype -589C-33C frequency (P < .05) in metastatic RCC compared with other white reference study populations. The median overall survival was decreased 3.5-fold (P < .05) in heterozygote patients carrying IL4 haplotype -589T-33T and -589C-33C (3.78 months) compared with patients homozygote for IL4 haplotype -589C-33C (13.44 months). In addition, a linkage disequilibrium between the IL4 gene and the KIF3A gene was detected.
Our findings indicate that IL4 promoter variants influence prognosis in patients with metastatic RCC and suggest that genetically determined interleukin-4 (IL-4) production affects the clinical course of the disease possibly through regulation of immune surveillance.
Journal of Clinical Oncology 03/2007; 25(7):845-51. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We evaluated tumor cell growth modulation by bee venom secretory phospholipase A2 (bv-sPLA2) and phosphatidylinositol-(3,4)-bisphosphate as well as potential cooperative effects. In addition, the immunomodulatory impact of tumor cell treatment was examined by monitoring changes in phenotype and function of monocyte-derived dendritic cells (moDCs) cocultured with pretreated tumor cells. Bv-sPLA2 or phosphatidylinositol-(3,4)-bisphosphate alone displayed moderate effects on the proliferation of A498 renal cell carcinoma cells, T-47D breast cancer cells, DU145 prostate cancer cells and BEAS-2B transformed lung cells. However, when bv-sPLA2 was coadministered with phosphatidylinositol-(3,4)-bisphosphate a potent inhibition of [3H] thymidine incorporation into all tested cell lines occurred. This inhibition was due to massive cell lysis that reduced the number of cells with proliferative capacity. Importantly, tumor cell lysates generated with bv-sPLA2 plus phosphatidylinositol-(3,4)-bisphosphate induced maturation of human moDCs demonstrated by enhanced expression of CD83 and improved stimulation in allogeneic mixed leukocyte reactions. Our data demonstrate that bv-sPLA2 and phosphatidylinositol-(3,4)-bisphosphate synergistically generate tumor lysates which enhance the maturation of immunostimulatory human monocyte-derived dendritic cells. Such tumor lysates which represent complex mixtures of tumor antigens and simultaneously display potent adjuvant properties meet all requirements of a tumor vaccine.
Cancer Immunology and Immunotherapy 12/2006; 55(11):1374-83. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While previous reports clearly demonstrated antiproliferative effects of IL-4 on renal cell carcinoma (RCC) in vitro, the administration of IL-4 to patients with metastatic RCC in clinical trials could not recapitulate the promising preclinical results. In the present study we wanted to examine the context of IL-4 action and to establish conditions of enhanced IL-4 efficacy.
Primary and permanent human RCC cells were cultured in either serum-supplemented or chemically defined, serum-free culture medium in the presence or absence of cytokines. Cell proliferation was assessed as [(3)H]-thymidine incorporation. Cell apoptosis was measured using the fluorescent DNA intercalator 7-aminoactinomycin D and flow cytometry. In addition, culture media conditioned by RCC were subjected to cytokine antibody array and cytokine multiplex analysis.
Our results indicate that the previously reported antiproliferative effects of IL-4 are serum-dependent. Under serum-free conditions, IL-4 failed to exhibit growth-inhibitory effects or was even growth-stimulatory. In a chemically defined, serum-free medium (AIM-V), however, IL-4 inhibited the TNF-alpha induced proliferation of RCC. IL-4 and TNF-alpha synergistically induced apoptosis of RCC as well as a complex cytokine response by RCC, which included the synergistic upregulation of RANTES and MCP-1.
IL-4 alone has little effect on the spontaneous proliferation of RCC but can prevent the enhancement of proliferation induced by growth promoters like FBS and TNF-alpha. The concomitant growth inhibitory, apoptosis-inducing, and cytokine-enhancing effects of IL-4 in combination with TNF-alpha on RCC support the view that Th2 cytokines may be required for productive immune responses against RCC.
Cancer Immunology and Immunotherapy 11/2006; 55(10):1228-37. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IntroductionPhytoestrogen apigenin, a member of flavonoids, has been described for its ability to induce growth arrest in carcinomas of colon, breast and prostate. In order to identify its influence on the prostatic stroma, which plays a crucial role in the pathogenesis of benign prostatic hyperplasia (BPH), we investigated the effect of apigenin on cell proliferation and cell-cycle progression.Methods
Prostatic stromal cells were isolated from nonmalignant tissue specimens obtained from patients undergoing radical prostatectomy. After incubation with increasing concentrations of apigenin for 24, 48 and 72 h the cell proliferation was determined by MTT assay. Cell-cycle regulation was examined by FACS analysis and the expression level of proteins involved in the G1/S transition was determined by immunoblot analysis.ResultsApigenin treatment resulted in a significant inhibition of proliferation starting at a concentration of 30 μM of the flavonoid. FACS analysis showed cell-cycle arrest at a G1/S transition point. Furthermore, apigenin modified the expression levels of cell-cycle regulatory proteins leading to a dose-dependent decrease of cyclin D1 and an increase of p21/WAF1 expression, as determined by immunoblot analysis. As apigenin lead to a decrease of the phosphorylation status of ERK1 and 2, we postulated that the mechanism of apigenin action is mediated through mitogen activated kinases (MAPK)-pathway.Conclusion
Taken together, in response to apigenin treatment prostatic stromal cells showed a dose-dependent inhibition of cell proliferation, which may be due to a cell-cycle growth arrest and seems to occur via MAPK-pathway. These results suggest possible beneficial effects of apigenin in the prevention and/or treatment of benign prostatic hyperplasia.