Hormonal manipulation of benign prostatic hyperplasia

Rick, Ferenc G.; Saadat, Seyed Hassan; Szalontay, Luca; Block, Norman L.; Kazzazi, Amir; Djavan, Bob; Schally, Andrew V.

doi:10.1097/mou.0b013e32835abd18

Cited by 19 publications

(14 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A great advantage of GRP antagonist is the lack of known adverse effects, contrary to finasteride. Because our GRP antagonist seems to have similar effects on the prostate as finasteride (prostate shrinkage through reduction in the epithelial compartment, increase in apoptosis), a combination of GRP antagonist with α-adrenoreceptor blockers (ABs) such as doxasosin would be a good choice based on information emerging from clinical trials on combinations of an 5-ARI and an AB (MTOPS, CombAT) (23).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Rick

Abi-Chaker

Szalontay

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Gastrin releasing-peptide (GRP) is a potent growth factor in many malignancies. Benign prostatic hyperplasia (BPH) is a progressive age-related proliferation of glandular and stromal tissues; various growth factors and inflammatory processes are involved in its pathogenesis. We have demonstrated that potent antagonists of GRP inhibit growth of experimental human tumors including prostate cancer, but their effect on models of BPH has not been studied. Here, we evaluated the effects of GRP antagonist RC-3940-II on viability and cell volume of BPH-1 human prostate epithelial cells and WPMY-1 prostate stromal cells in vitro, and in testosterone-induced BPH in Wistar rats in vivo. RC-3940-II inhibited the proliferation of BPH-1 and WPMY-1 cells in a dosedependent manner and reduced prostatic cell volume in vitro. Shrinkage of prostates was observed after 6 wk of treatment with RC-3940-II: a 15.9% decline with 25 μg/d; and a 18.4% reduction with 50 μg/d (P < 0.05 for all). Significant reduction in levels of proliferating cell nuclear antigen, NF-κβ/p50, cyclooxygenase-2, and androgen receptor was also seen. Analysis of transcript levels of genes related to growth, inflammatory processes, and signal transduction showed significant changes in the expression of more than 90 genes (P < 0.05). In conclusion, GRP antagonists reduce volume of human prostatic cells and lower prostate weight in experimental BPH through direct inhibitory effects on prostatic GRP receptors. GRP antagonists should be considered for further development as therapy for BPH.bombesin | cell volume measurement | prostatic inflammation | rodent benign prostatic hyperplasia model | targeted therapy H ormonal polypeptides, bombesin (BN) and gastrin-releasing peptide (GRP), can act as autocrine and paracrine growth factors, and regulate cellular growth, differentiation, and apoptosis (1, 2). Tetradecapeptide bombesin was isolated from the skin of the European fire-bellied toad (Bombina bombina) (3), and subsequently, two mammalian bombesin-like peptides were characterized: GRP and neuromedin B (NMB) (4). GRP and BN influence the secretion of gastrointestinal hormones, stimulate the release of gastrin and somatostatin, induce pancreatic exocrine secretion (5), and induce contractions of the smooth muscle of the stomach, gall bladder, uterus, urinary bladder, and prostate (6). GRP was first shown to be a mitogen for Swiss 3T3 murine embryonal fibroblasts and, subsequently, for a number of normal cell types and cancers in vivo and in cell culture (7). GRP is now recognized as the prototypical autocrine growth factor, based on the detection of GRP and its receptors in small cell lung carcinoma and other tumors (8). GRP was shown to stimulate growth of several other types of carcinomas including those of prostate, breast, colon, and pancreas (9). Three different receptor subtypes for the BN/GRP family of peptides have been described in mammals (10). Receptor subtype 1 (termed GRP-R or BB 2 ) binds BN, GRP, and GRP antagonist RC-3940-II with high affinity (11). ...

show abstract

Section: Discussionmentioning

confidence: 99%

“…Despite the vast burden on public health, the pathogenesis of BPH remains undetermined. A variety of growth factors and inflammatory processes are inculpated in its pathogenesis (23).…”

mentioning

confidence: 99%

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Rick

Abi-Chaker

Szalontay

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the periphery, the LHRH system regulates gonadal functions and appears to serve as a growth factor of benign conditions [14-17] and various cancers including breast, lung, ovary, endometrial, kidney, bladder, colon, pancreas and prostate [18-25]. A specific, medium to high-affinity binding site for an LHRH agonist was found in 86% of prostate cancers [23].…”

Section: Introductionmentioning

confidence: 99%

Targeted cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), AEZS-108 (AN-152), inhibits the growth of DU-145 human castration-resistant prostate cancerin vivoandin vitrothrough elevating p21 and ROS levels

et al. 2014

Self Cite

View full text Add to dashboard Cite

Management of castration-resistant prostate cancer (CRPC) is challenging due to lack of efficacious therapy. Luteinizing hormone-releasing hormone (LHRH) analogs appear to act directly on cells based on the LHRH receptors on human prostate adenocarcinoma cells. We explored anticancer activity of a cytotoxic analog of LHRH, AEZS-108, consisting of LHRH agonist linked to doxorubicin. Nude mice bearing DU-145 tumors were used to compare antitumor effects of AEZS-108 with its individual constituents or their unconjugated combination. The tumor growth inhibition of conjugate was greatest among treatment groups (90.5% inhibition vs. 41% by [D-Lys(6)]LHRH+DOX). The presence of LHRH receptors on DU-145 cells was confirmed by immunocytochemistry. In vitro, AEZS-108 significantly inhibited cell proliferation (61.2% inhibition) and elevated apoptosis rates (by 46%). By the detection of the inherent doxorubicin fluorescence, unconjugated doxorubicin was seen in the nucleus; the conjugate was perinuclear and at cell membrane. Autophagy, visualized by GFP-tagged p62 reporter, was increased by AEZS-108 (7.9-fold vs. 5.3-fold by DOX+[D-Lys(6)]LHRH. AEZS-108 more effectively increased reactive oxygen species (ROS, 2-fold vs. 1.4-fold by DOX+[D-Lys(6)]LHRH) and levels of the apoptotic regulator p21 in vivo and in vitro. We demonstrate robust inhibitory effects of the targeted cytotoxic LHRH analog, AEZS-108, on LHRHR positive castration-resistant prostate cancer cells.

show abstract

“…Hypothalamic neurohormone GHRH and GHRH-R are not confined to the hypothalamic-pituitary axis, however, but are also produced by various extrahypothalamic sites. GHRH/GHRH-R modulates cell proliferation and apoptosis in many tissues, including prostate (8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

Fahrenholtz

Rick

García

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Advanced hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists-MIA-602, MIA-606, and MIA-690-on the growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC.androgen-independent | G protein-coupled receptor | hypothalamic neurohormone | neuropeptide | targeted therapy

show abstract

Hormonal manipulation of benign prostatic hyperplasia

Cited by 19 publications

References 69 publications

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Shrinkage of experimental benign prostatic hyperplasia and reduction of prostatic cell volume by a gastrin-releasing peptide antagonist

Targeted cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), AEZS-108 (AN-152), inhibits the growth of DU-145 human castration-resistant prostate cancerin vivoandin vitrothrough elevating p21 and ROS levels

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

Contact Info

Product

Resources

About