Biomedical subjects

Fouad K Habib

Publications and source records attributed to Fouad K Habib.

7 recordsLinked to original sources

PubMed2005

Polymorphic forms of prostate specific antigen and their interaction with androgen receptor trinucleotide repeats in prostate cancer.

BACKGROUND: Recent data has suggested that polymorphisms in the prostate specific antigen (PSA) may increase prostate cancer (PC) risk. The PSA gene contains a G/A substitution in the androgen response element (ARE) 1 region. The androgen receptor (AR) gene has polymorphic regions containing variable length glutamine and glycine repeats and these are believed to be associated with PC risk. The effect on PC risks from PSA polymorphisms alone and synergistically with the AR gene was examined in this report. METHODS: One hundred PC patients and an age matched cohort of 79 benign prostate hyperplasia and 67 population controls were entered in this study. DNA was extracted from blood and PSA/ARE promoter region amplified by PCR. PCR products were cut with Nhe 1 restriction enzyme to distinguish G/A alleles. AR/CAG and GGC repeat length was detected by automated fluorescence from PCR products. RESULTS: We found a significantly higher PSA/GG distribution in PC (30%) than either benign prostatic hyperplasia (BPH) (18%) or population controls (16%) (P = 0.025). Furthermore the GG distribution within cases was even greater in younger men (< 65 years; 42%; P = 0.012). Additionally, when PSA genotype was cross classified with CAG repeat, significantly more cases than both BPH and population controls were observed to have a short (< 22) CAG/GG genotype (P = 0.006). CONCLUSIONS: Our results indicate that the PSA/ARE GG genotype confers an increased risk of PC especially among younger men. Moreover, we confirm previous results that a short glutamine repeat in conjunction with GG genotype significantly increases the risk of malignant disease.

Aged↗

PubMed2005

Serenoa repens (Permixon) inhibits the 5alpha-reductase activity of human prostate cancer cell lines without interfering with PSA expression.

The phytotherapeutic agent Serenoa repens is an effective dual inhibitor of 5alpha-reductase isoenzyme activity in the prostate. Unlike other 5alpha-reductase inhibitors, Serenoa repens induces its effects without interfering with the cellular capacity to secrete PSA. Here, we focussed on the possible pathways that might differentiate the action of Permixon from that of synthetic 5alpha-reductase inhibitors. We demonstrate that Serenoa repens, unlike other 5alpha-reductase inhibitors, does not inhibit binding between activated AR and the steroid receptor-binding consensus in the promoter region of the PSA gene. This was shown by a combination of techniques: assessment of the effect of Permixon on androgen action in the LNCaP prostate cancer cell line revealed no suppression of AR and maintenance of PSA protein expression at control levels. This was consistent with reporter gene experiments showing that Permixon failed to interfere with AR-mediated transcriptional activation of PSA and that both testosterone and DHT were equally effective at maintaining this activity. Our results demonstrate that despite Serenoa repens effective inhibition of 5alpha-reductase activity in the prostate, it did not suppress PSA secretion. Therefore, we confirm the therapeutic advantage of Serenoa repens over other 5alpha-reductase inhibitors as treatment with the phytotherapeutic agent will permit the continuous use of PSA measurements as a useful biomarker for prostate cancer screening and for evaluating tumour progression.

5-alpha Reductase Inhibitors↗

PubMed2004

Androgen receptor protein expression in prostatic tissues in Black and Caucasian men.

BACKGROUND: CaP has a higher incidence and mortality in Black men. We hypothesized that subpopulation differences in AR expression may contribute to this phenomenon. METHOD: AR immunostaining was compared in epithelium and PES of normal, BPH, and CaP tissues from Black African men and UK Caucasian men. RESULTS: AR expression was similar in normal prostatic epithelium of both groups, but was higher in BPH and CaP epithelium of Black than Caucasian men (P </= 0.0001). Also, AR expression in PES was higher in Caucasian than Black men in normal/atrophic and benign hyperplastic tissues, but there was a similar significant loss of AR expression in PES of CaP tissues of both groups (normal and BPH stroma versus CaP stroma (P </= 0.0001). CONCLUSIONS: Variations in AR expression between subpopulations may contribute to the phenotypic differences of prostatic diseases in Black and Caucasian men.

Black People↗

PubMed2004

Nitric oxide donating nonsteroidal anti-inflammatory drugs induce apoptosis in human prostate cancer cell systems and human prostatic stroma via caspase-3.

PURPOSE: New nitric oxide (NO) donating nonsteroidal anti-inflammatory drugs (NSAIDs) have been synthesized to counteract the side effects of conventional NSAIDs. Mounting evidence suggests that NSAIDs may have a possible chemopreventative/therapeutic role in prostate cancer. NO is a powerful biological messenger with multiple cellular effects. We established the effects of 2 of these new drugs in prostate cell systems. MATERIALS AND METHODS: We studied the effects of NO-ibuprofen (NCX 2111) and NO-aspirin (NCX 4060) on hormone sensitive (LNCap) and insensitive (PC3) prostate cancer epithelial cell lines as well as primary cultures of prostatic stroma. Proliferation was measured using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazalium bromide) assay to examine proliferation. Subsequently flow cytometry, cell cycle analysis and TUNEL staining were used to look for apoptosis. Caspase-3 expression was also examined in treated cell types. RESULTS: NCX 2111 and NCX 4060 were found to be potent inhibitors of proliferation in a dose dependent fashion. The 2 drugs induced apoptosis, as seen by flow cytometry, cell cycle analysis and TUNEL staining, at doses between 10 and 100 microM. These NO-NSAIDs increased caspase-3 expression. NCX 4060 was more effective at lower concentrations (10 microM) but each compound was much more potent than conventional ibuprofen and aspirin at inducing apoptosis and inhibiting proliferation. CONCLUSIONS: NO-NSAIDs are potent antiproliferative pro-apoptotic compounds in prostate cell systems. This pro-apoptotic effect is mediated via caspase-3 and it is independent of the type of prostate cell used. These findings have ramifications for the use of these new drugs in prostate cancer chemoprevention or treatment.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2004

Quantitative morphometric analysis of individual resected prostatic tissue specimens, using immunohistochemical staining and colour-image analysis.

OBJECTIVE: To develop a method for obtaining morphometric measurements representative of individual chips from transurethral resection of the prostate (TURP). MATERIALS AND METHODS: In all, 232 sections were cut in pairs from 25 TURP chips, collected from four patients undergoing TURP for benign prostatic hyperplasia. Individual tissue chips were processed, embedded in paraffin wax and pairs of neighbouring sections cut from the specimens at intervals of 300 microm throughout the thickness of the specimen. Of each pair, the epithelial tissue (ET) of one and the smooth muscle (SM) of the other section were stained immunohistochemically with anti-prostate-specific antigen and anti-SM myosin, respectively. Proportions of ET and SM within the sections were measured with colour-image analysis and calculated within the TURP chips using all pairs of sections cut from the specimen, and the first pair of sections only. The differences between the sets of results were analysed using descriptive statistics. RESULTS: From each TURP chip, 3-7 pairs of sections were cut; for both ET and SM within each chip the differences between the results calculated using data from all pairs of sections and the first pair alone were small, as were the distributions of these differences within each prostate. CONCLUSIONS: Morphometric measurements from one section from a processed TURP chip, as opposed to serial sections, can be used to reliably assess the morphology of tissue within that specimen. This permits a considerable saving of resources when undertaking morphometric image analysis of resected prostatic tissue specimens.

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PubMed2004

CYP7B generates a selective estrogen receptor beta agonist in human prostate.

In human prostate, dehydroepiandrosterone (DHEA) is a substrate for two major metabolic pathways that produce functionally opposing sex steroids. In one pathway, DHEA is converted into potent androgens such as testosterone and 5alpha-dihydrotestosterone. In the other, DHEA is metabolized to 7alpha-hydroxy-DHEA (7HD). Recently, CYP7B, a novel P450 enzyme originally characterized in mouse brain and expressed in rodent prostate, has been found to be responsible for all extrahepatic 7alpha-hydroxylase activity. In this study, we have investigated the expression and function of this novel enzyme in human prostate. We have used reverse transcription combined with PCR and mRNA in situ hybridization to determine and localize the expression of CYP7B mRNA in human benign prostatic hyperplasia. High levels of CYP7B mRNA were localized in the epithelial cells together with estrogen receptor beta (ERbeta). 7alpha-Hydroxylation was the major metabolic fate of DHEA in human prostate. Furthermore, we have shown that human prostate epithelial cells in primary culture maintain a high level of 7alpha-hydroxylase activity, which was enhanced by coculture with stroma cells. To investigate the functional relevance of CYP7B expression to sex-steroid action in prostate, we used transient transfections and ligand binding assay to determine the ability of 7HD to bind and activate the sex-steroid receptors: androgen receptor, ERalpha, and ERbeta. 7HD specifically activates ERbeta-mediated transcription, mimicking the effects of 17beta-estradiol, but has no impact on ERalpha and androgen receptor. Given that DHEA, and its sulfate, circulate at micromolar concentrations, there is a clear possibility that CYP7B generates sufficient 7HD to activate ERbeta over and above that achieved with very low concentrations of intraprostatic 17beta-estradiol. In conclusion, our study suggests that CYP7B catalyzes oxysterol 7alpha-hydroxylation within the human prostate epithelium. By this reaction, an ERbeta-specific agonist, 7HD, is produced. Therefore, CYP7B may be a novel regulator of the androgens/estrogenic balance within the prostate.

Aged↗

PubMed2003

The loss of 5alpha-reductase type I and type II mRNA expression in metastatic prostate cancer to bone and lymph node metastasis.

PURPOSE: Considerable evidence has accumulated demonstrating that the 5alpha-reduction of testosterone to dihydrotestosterone occurs more efficiently in the normal and benign hyperplastic prostate than in prostate cancer tissues. Efforts have also been channeled into investigating the distribution of 5alpha-reductase isoenzymes in primary prostate tissues and in "in vitro" cell models of the human prostate. However, no one has, thus far, examined the expression of these isoenzymes in prostate cancer metastasis, although such studies might shed some light on the mechanism(s) responsible for the loss of hormone sensitivity in those tumors. The present report addresses this issue in the hope that this might help to identify the steps leading to the development of prostate cancer metastasis. EXPERIMENTAL DESIGN: In the present study we used in situ mRNA hybridization of sections from archival paraffin-embedded material to investigate the expression of 5alpha-reductase type I (5alphaR-I) and type II (5alphaR-II) mRNAs in prostate cancer bony (n = 9) and lymph node (n = 13) metastasis, and compared the mRNA distributions with those observed in sections from primary prostate tumors (n = 12). In parallel, sections were investigated for androgen receptor (AR) mRNA expression, and immunostained for AR and prostate-specific antigen. RESULTS: Neither 5alphaR-I nor 5alphaR-II mRNA expression was detected in any of the prostate metastatic lesions, although the same metastatic sites expressed AR mRNA, and stained for cytoplasmic prostate-specific antigen and nuclear AR. In contrast, primary prostate tumors displayed intense staining for 5alphaR-I and 5alphaR-II. CONCLUSION: These findings suggest that the loss of 5alpha-reductase mRNA expression in bone and lymph node metastasis may be associated, in part, with the progression of these tumors to androgen insensitivity.

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