Effects of 5 alpha reductase inhibitors on androgen-dependent human prostatic carcinoma cells

Festuccia, Claudio; Angelucci, Adriano; Gravina, Giovanni Luca; Muzi, Paola; Vicentini, Carlo; Bologna, Mauro

doi:10.1007/s00432-004-0632-1

Cited by 7 publications

(4 citation statements)

References 47 publications

(48 reference statements)

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“…There were no significant changes in the percentages of treated primary responder and nonresponder epithelial cells that progressed to G 2 M-phase of the cell cycle after treatment for 24 hours. In a recent study, Festuccia et al 31 showed that dual inhibition of both 5 ␣-reductase enzymes by MK906 (Finasteride) and MK386 in primary cultures of prostate cancer cells (that contained both fibroblast/stromal cells and epithelial cells) induced several morphologic changes and demonstrated growth inhibition. In addition, inhibition of growth also was observed in the same study in LNCaP cells that were cocultured with prostate cancer fibroblasts and in LNCaP cells that were cocultured with fibroblasts or stroma derived from BPH specimens.…”

Section: 12mentioning

confidence: 99%

Effects of the dual 5 α‐reductase inhibitor dutasteride on apoptosis in primary cultures of prostate cancer epithelial cells and cell lines

McCrohan

Morrissey

O’Keane

et al. 2006

Cancer

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BACKGROUNDThe profound reduction in serum dihydrotestosterone (DHT) observed with the dual 5 α‐reductase inhibitor (5ARI) dutasteride makes it an attractive agent for prostate cancer therapy. The objective of the current study was to determine whether dutasteride would induce apoptosis in a range of prostate epithelial cell lines and primary cultures.METHODSBoth human prostate androgen‐sensitive cell lines (PwR‐1E, PNT‐2, LNCaP, and PC3[AR2]) and an androgen‐independent cell line (PC‐3) were grown to confluence. Primary epithelial cells extracted from fresh prostate cancer radical prostatectomy specimens also were grown to confluence under optimal conditions. Total cellular protein was extracted to confirm cytokeratin 18 and antihuman α‐methylacyl‐CoA racemase (AMACR) expression of the primary cells. Apoptosis was assessed by propidium iodide DNA staining and flow cytometry after 24 hours of culture in from 0 μM to 10 μM of dutasteride.RESULTSDutasteride induced a dose‐dependent increase in apoptosis in the androgen‐sensitive prostate cell lines PwR‐1E, PNT‐2, and LNCaP and in the androgen receptor‐expressing PC3(AR2) cell line. However, there was no significant apoptosis noted in the parental PC‐3 cells. Of 16 primary epithelial cultures that were treated, 7 cultures were induced to undergo apoptosis, and 9 cultures were unresponsive. All primary cultures were positive for cytokeratin 18 expression, confirming their epithelial phenotype. Responder epithelial cells were positive for AMACR expression.CONCLUSIONSThe results of the current study confirmed that dutasteride differentially induced apoptosis in a subset of prostate cell lines and primary prostate epithelial cells. Understanding the cellular phenotype may indicate susceptible cells. Cancer 2006. © 2006 American Cancer Society.

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Section: 12mentioning

confidence: 99%

Effects of the dual 5 α‐reductase inhibitor dutasteride on apoptosis in primary cultures of prostate cancer epithelial cells and cell lines

McCrohan

Morrissey

O’Keane

et al. 2006

Cancer

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“…This might be expected for transit amplifying cells, however, is in contrast to a few other published studies. Festuccia et al for instance found moderate high levels of AR, PSA and KlK2 in outgrowing cells from prostate tissue clumps (16) and a decreased cell proliferation upon treatment with 5-·-reductase inhibitors (17). Moreover, bicalutamide was shown to decrease cell viability in a dosedependent manner (18).…”

Section: Discussionmentioning

confidence: 99%

Primary prostate cancer cultures are models for androgen-independent transit amplifying cells

Bühler

Wolf²,

Katzenwadel³

et al. 2009

Oncol Rep

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Abstract. Numerous efforts exist for developing primary prostate cancer cultures for studying the biology of this tumor entity and for evaluation of the effectiveness of novel therapies. However, there is doubt if cultures that represent the fully differentiated phenotype can be established. The aim of the present study was to characterize primary outgrowing prostate epithelial cells due to their basal or luminal characteristics and their potential for serving as androgen-responsible model. From fresh prostate cancer radical prostatectomy specimens, pieces of ~2-4 mm diameter were placed on top of transwell culture chambers, which were coated with matrigel and cultured in prostate epithelial selection medium with 10% fetal calf serum. The monolayer of outgrowing cells was incubated with a physiological concentration of 1 nM dihydrotestosterone (DHT). One group was additionally cultivated without DHT and another group was treated with the 5-·-reductase-inbitors MK-368 and MK-905. From the monolayer of the outgrowing cells, RNA was isolated and the expression of androgen receptor (AR), prostate-specific antigen (PSA), Kallikrein 2 (KlK2), prostate-specific membrane antigen (PSMA), and prostate stem cell antigen (PSCA), cytokeratin (CK)5, and CK18 was determined by realtime quantitative PCR. The outgrowing cells from the prostate cancer tissue pieces could be characterized as epithelial cells with basal and transit amplifying characteristics as shown by co-expression of CK5 and CK18. In all cultures, a very low expression of the luminal cell marker genes AR, PSA and KLK2 was measured. The levels of PSCA were clearly higher with a broad variation. Upon cultivation without DHT or treatment with ·-reductase inhibitors no regulation of AR, PSA and KlK2 was found. Due to the co-expression of basal and luminal marker genes, primary prostate cancer cultures can be charaterized as models of transit amplifying cells of the prostatic epithelium. They do not represent the differentiated secretory androgen-responsive cell phenotype.

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“…8 The application of inhibitors of the 5a-R1 and 5a-R2 isoforms in cultures of primary prostate cancer decreased the cell proliferation dose-dependently through auto-or paracrine mechanisms. 53 When patients are treated with Dutasteride 6-10 weeks before radical prostatectomy the intraprostatic DHT 5a-Reductase inhibitor treatment J Dörsam and J Altwein was reduced by 97% and apoptosis was augmented possibly indicating tumor regression. 52 The effect of androgen deprivation on prostate cancer tissue was also investigated.…”

Section: Chemoprevention Of Prostate Cancermentioning

confidence: 99%

5α-Reductase inhibitor treatment of prostatic diseases: background and practical implications

Dörsam¹,

Altwein

2008

Prostate Cancer Prostatic Dis

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This literature review discusses the theoretical background of 5a-reductase inhibitor (5ARI) treatment and the resulting clinical implications. A Medline-based search for peer-reviewed articles addressing 5ARIs, benign prostatic hyperplasia and prostate cancer was performed. The 5ARIs Finasteride and Dutasteride, which specifically inhibit the production of dihydrotestosterone by acting as competitive inhibitors of 5a-reductase, are clinically well tolerated and represent an effective treatment option for benign prostatic obstruction. Finasteride is the first compound which has a proven efficacy in chemoprevention of prostate cancer. The aim of this review was to elucidate, if there are sufficient data available to point out clinically relevant differences between the drugs. Both compounds achieve a significant reduction of prostate volume, an improvement of symptoms and a lower risk of acute urinary retention. Whether the different pharmacokinetic and pharmacodynamic properties of Finasteride and Dutasteride are of clinical importance cannot be judged at this time.

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Effects of 5 alpha reductase inhibitors on androgen-dependent human prostatic carcinoma cells

Cited by 7 publications

References 47 publications

Effects of the dual 5 α‐reductase inhibitor dutasteride on apoptosis in primary cultures of prostate cancer epithelial cells and cell lines

Effects of the dual 5 α‐reductase inhibitor dutasteride on apoptosis in primary cultures of prostate cancer epithelial cells and cell lines

Primary prostate cancer cultures are models for androgen-independent transit amplifying cells

5α-Reductase inhibitor treatment of prostatic diseases: background and practical implications

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