tretinoin and Prostatic-Hyperplasia

In 2010, the FDA approved several new drugs and new indications for use in primary care. From new therapies for adults with rheumatoid arthritis to a combination drug for benign prostatic hyperplasia, NPs need to be aware of the latest medications now available.

Topics: Amlodipine; Antihypertensive Agents; Azasteroids; Clindamycin; Dermatologic Agents; Drug Combinations; Dutasteride; Humans; Hydrochlorothiazide; Imidazoles; Male; Prostatic Hyperplasia; Sulfonamides; Tamsulosin; Tetrazoles; Tretinoin; United States; United States Food and Drug Administration

The human prostate gland is a well known source of H1 and H2 relaxin but information is lacking on the expression and potential role of the INSL3 peptide hormone within the prostate gland. In the present study we have investigated the expression of human INSL3 in patients with benign prostate hyperplasia (BPH), prostate intraepithelial neoplasia (PIN) and prostate carcinoma tissues. Of the prostate epithelial cells, strongest INSL3 expression was detected in the basal epithelial cell compartment. Weaker INSL3 mRNA expression and immunoreactive INSL3 production were observed in secretory epithelial cells and in interstitial smooth muscle cells. Prostate epithelial cells were also a source for transcripts encoding the INSL3 receptor LGR8 suggesting the presence of an autocrine/paracrine INSL3-LGR8 ligand-receptor system within the human prostate. Three human prostate carcinoma cell lines displayed differential gene activity for INSL3 and LGR8. While LNCaP was devoid of INSL3, the androgen-insensitive PC-3 and the stromal prostate cell line hPCP co-expressed INSL3 and LGR8 transcripts. In addition to expressing INSL3 mRNA, the LGR8-negative DU-145 also expressed an INSL3 splice form formerly demonstrated in thyroid carcinoma cells. When incubated with recombinant INSL3, PC-3 cells showed significantly increased intracellular cAMP levels indicating functional LGR8 receptors. INSL3 did not alter the proliferative or metabolic activity of PC-3 carcinoma cells. Instead, PC-3 responded to INSL3 with significantly enhanced tumor cell motility and a transcriptional down-regulation of ErbB receptors and EGF. All-trans-retinoic acid was demonstrated in PC-3 to up-regulate LGR8 gene activity in a dose- and time-dependent manner while having no effect on INSL3 gene activity. In conclusion, we have identified a functional INSL3-LGR8 ligand-receptor system in human prostate carcinoma cells.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cyclic AMP; Dose-Response Relationship, Drug; Epidermal Growth Factor; Epithelial Cells; Gene Expression; Humans; Immunohistochemistry; In Situ Hybridization; Insulin; Male; Prostatic Hyperplasia; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms; Proteins; Receptors, G-Protein-Coupled; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Tretinoin

Changes in circulating levels of insulin-like growth factors (IGF) and IGF-binding proteins (IGFBP) have been related to prostate cancer, but the nature and the significance of this relationship remains elusive. Recent reports suggest that modulation of the production of IGFBP-3 by retinoids may affect growth of breast and prostate tumor cells. In the present study we explored whether androgens (R1881), retinoids (all-trans- and 9-cis-retinoic acid: atRA and 9cRA), deltanoids (1alpha,25-dihydroxycholecalciferol: VD3) and thyroid hormone (triiodothyronine: T3) influence the production of IGFBPs by LNCaP prostatic adenocarcinoma cells and whether the observed changes affect tumor cell growth. Northern blot experiments demonstrated that LNCaP cells express IGFBP-2, -3, -4 and (to a small extent) -5. IGFBP-4 and -5 were not measurably affected by the mentioned agonists. At a growth promoting concentration (10(-10) M), R1881 increased IGFBP-2 transcript levels two- to three-fold and this effect was neutralized by atRA and VD3. Similar effects could not be demonstrated, however, at the protein level using Western ligand blotting. R1881 decreased and atRA increased the mRNA levels of IGFBP-3 and these effects were confirmed by Western ligand blotting and by radioimmunoassay. The effects of atRA were mimicked by 9cRA and by a specific RAR agonist but not by a RXR agonist. VD3 and T3 had no significant effect on IGFBP-3 secretion but respectively enhanced or decreased the effect of 9cRA. The effects of retinoids required high concentrations (10(-6)-10(-5) M) that also induced growth inhibition. R1881, however, decreased IGFBP-3 at growth promoting (10(-10) M) as well as at growth inhibitory (10(-8) M) concentrations. Moreover, under serum-free conditions, we were unable to demonstrate any growth modulating effect of IGFBP-3. It is concluded that several agonists acting by nuclear receptors affect IGFBP-3 secretion by LNCaP cells but that the functional significance of these changes warrants further investigation.

Topics: Adenocarcinoma; Calcitriol; Cell Division; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Humans; Insulin-Like Growth Factor Binding Protein 3; Male; Metribolone; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Retinoids; Testosterone Congeners; Tretinoin; Triiodothyronine; Tumor Cells, Cultured

Vitamin A (retinol) and its derivatives, the retinoids, have been implicated as chemopreventive and differentiating agents in a variety of cancers, including that of the prostate. Very little is known about the physiological role of retinoids in the prostate. Here we show that normal prostate, benign prostate hyperplasia (BPH), and prostate carcinoma tissues contain endogenous retinol and its biologically active metabolite retinoic acid. In our studies, the concentration of retinol was 2-fold elevated in BPH compared with the other two tissues. In contrast, prostate carcinoma tissue contained five to eight times less retinoic acid than normal prostate or BPH. Moreover, we found that prostate tissue expresses dehydrogenases capable of converting retinol to retinoic acid through retinaldehyde as an intermediate. Formation of retinal from retinol takes place in microsomes, and the conversion of retinal to retinoic acid occurs in the cytosol. Furthermore, we found that the nuclear retinoic acid receptors alpha, beta, and gamma are expressed in normal and tumor samples. These studies establish a role for retinoids in the physiology of the prostate and possibly also in the pathophysiology of prostate cancer.

Topics: Base Sequence; Chromatography, High Pressure Liquid; Humans; Male; Molecular Probes; Molecular Sequence Data; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Retinoic Acid; Reference Values; Retinaldehyde; Retinoids; RNA, Messenger; Tretinoin; Vitamin A

Expression of certain cytokeratins can be indicative of the state of differentiation of epithelial cells. The basal cells in the normal adult human prostatic epithelium are characterized by the expression of cytokeratins 5 and 14, whereas the secretory luminal cells contain cytokeratins 8 and 18. Cells cultured from the prostatic epithelium expressed cytokeratins 5, 8, and 18, and thus had features of both basal and luminal cells. Certain growth-inhibitory conditions altered keratin expression in conjunction with growth modulation. Deletion of peptide factors and hormones from the culture medium induced the expression of cytokeratins 1 and 10, associated with a squamous phenotype. These same squamous keratins were found in very dense, stratified cultures that were maintained at confluency in standard, complete medium for extended periods. Retinoic acid enhanced the expression of secretory luminal cell-associated cytokeratins 8 and 18 in semi-confluent cultures. Other growth inhibitory factors such as suramin, transforming growth factor-beta, and interferon-gamma had no effect on keratin expression. These observations indicate that the differentiation of prostatic epithelial cells can be directed toward alternate pathways, either squamous or secretory, by different growth-inhibitory conditions. However, not all growth inhibitory factors altered differentiation, demonstrating that growth inhibition in itself is not a sufficient inducer of differentiation.

Topics: Cell Division; Cells, Cultured; Epithelial Cells; Epithelium; Glucose; Growth Substances; Humans; Interferon-gamma; Keratins; Male; Phenotype; Prostate; Prostatectomy; Prostatic Hyperplasia; Prostatic Neoplasms; Reference Values; Suramin; Transforming Growth Factor beta; Tretinoin

The response of cultured human prostatic epithelial cells to vitamin A was measured by clonal growth assay in serum-free medium. Retinoic acid at 3 nM or higher inhibited the proliferation of cell strains derived from normal, benign hyperplastic and malignant tissues, while lower levels (0.03 nM) were stimulatory. Reduced proliferation induced by retinoic acid was accompanied by a marked change in morphology, as intercellular adhesion decreased. In conjunction, the expression of keratins 8 and 18, associated with the differentiated luminal phenotype of prostatic epithelia, was increased. In post-confluent cultures, retinoic acid prevented the appearance of keratin 1, which accompanied the development of a squamous phenotype by cells maintained under these conditions. The findings of this study indicate a role for vitamin A as a modulator of the growth and differentiation of prostatic epithelial cells.

Topics: Cell Differentiation; Cell Division; Cells, Cultured; Epithelial Cells; Epithelium; Humans; Immunoblotting; Immunohistochemistry; Keratins; Male; Prostate; Prostatic Hyperplasia; Tretinoin; Vitamin A

The effect of retinoic acid (RA) on testosterone metabolic pathway was investigated in hyperplastic and neoplastic human prostatic tissues, and also the effects of steroids on RA binding to its receptor. Steroids only had a minimal effect on the binding of RA by its receptor. The conversion of testosterone to DHT by 5 alpha-reductase was reduced in the presence of retinoic acid. The inhibition was probably due to competition with NADPH for enzyme binding sites. The degree of inhibition found with retinoic acid at a concentration of 10(-4)M was greater for hyperplastic (41%) than that for neoplastic tissue (24%). The inhibition of 5 alpha-reductase by retinoic acid was dose-dependent. The activity of 5 alpha-reductase is significantly less in neoplastic compared with hyperplastic tissue.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Carrier Proteins; Humans; Male; NADP; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Retinoic Acid; Tretinoin

Prostate samples from 41 patients with acute on chronic prostatitis, benign hyperplasia, chronic prostatitis or adenocarcinoma were assayed for cytosolic retinoic acid binding protein (cRABP). Binding protein was detected in all samples. Scatchard analysis revealed dissociation constant values of 15.0-31.8 nM and maximum binding capacity of 5.2 +/- 2.0 (S.E.) pmol/mg protein. Using sucrose density gradient centrifugation, cRABP was quantitated and values varied from 1.2 to 12.5 pmol/mg protein. High levels (greater than 3.5 pmol/mg protein) were found in 28/41 samples. There was no correlation between the cRABP binding/mg protein and the volume (%) of glandular tissue (compared with stroma). While there was no significant difference in the quantities of cRABP in the different disease groups, there was a tendency for a progressive increase from acute on chronic prostatitis to chronic prostatitis, the highest levels being present in carcinoma.

Topics: Adenocarcinoma; Binding Sites; Carrier Proteins; Centrifugation, Density Gradient; Chromatography, Gel; Cytosol; Humans; Male; Neoplasm Proteins; Prostatic Hyperplasia; Prostatic Neoplasms; Prostatitis; Receptors, Retinoic Acid; Tretinoin

Topics: Animals; Estradiol; Estrogens; Estrone; Male; Mice; Organ Culture Techniques; Prostatic Hyperplasia; Testosterone; Tretinoin

Topics: Animals; Benzopyrenes; Male; Mice; Mitosis; Organ Culture Techniques; Prostate; Prostatic Hyperplasia; Tretinoin

Topics: Animals; Cell Division; Hyperplasia; Male; Mice; Organ Culture Techniques; Prostatic Hyperplasia; Testosterone; Tretinoin; Vitamin A