Inhibitory effects of antagonists of growth hormone releasing hormone on experimental prostate cancers are associated with upregulation of wild‐type p53 and decrease in p21 and mutant p53 proteins

Stangelberger, Anton; Schally, Andrew V.; Rick, Ferenc G.; Varga, József; Baker, Benjamin; Zarándi, Márta; Halmos, Gábor

doi:10.1002/pros.21458

Cited by 27 publications

(24 citation statements)

References 50 publications

(100 reference statements)

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“…Our observation of the transcriptional suppression of Cdkn1a/p21 and Cdkn2a/p16, factors involved in cell-cycle control and DNA damage repair, in PC-3 tumors after treatment with the GHRH antagonist JMR-132 are in line with our recent findings (17). The mRNA levels of the proapoptotic genes Bad and Bax were up-regulated, whereas the expression of antiapoptotic Bcl2 was lowered significantly, confirming our recent observations (28,47).…”

Section: Discussionsupporting

confidence: 92%

“…Direct mechanisms involved in the main antitumor effects of GHRH antagonists appear to be based on blocking the action of autocrine GHRH on tumors and inhibition of autocrine IGF-I/II production (6,9). We have demonstrated previously that GHRH antagonists inhibit the growth of diverse human tumors xenografted into nude mice, including androgen-dependent and -independent prostate cancers, and also suppress the tumoral growth factors EGF, FGF2, IGF-I, IGF-II, and VEGF-A (6,(14)(15)(16)(17)(18)(19)(20).…”

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confidence: 99%

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Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases

Rick

Schally

Szalontay

et al. 2012

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

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The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy of current therapies. Novel therapeutic strategies for the treatment of CRPC are needed. Antagonists of hypothalamic growth hormone-releasing hormone (GHRH) inhibit growth of various malignancies, including androgen-dependent and independent prostate cancer, by suppressing diverse tumoral growth factors, especially GHRH itself, which acts as a potent autocrine/paracrine growth factor in many tumors. We evaluated the effects of the GHRH antagonist, JMR-132, on PC-3 human androgen-independent prostate cancer cells in vitro and in vivo. JMR-132 suppressed the proliferation of PC-3 cells in vitro in a dose-dependent manner and significantly inhibited growth of PC-3 tumors by 61% ( P < 0.05). The expression of GHRH, GHRH receptors, and their main splice variant, SV1, in PC-3 cells and tumor xenografts was demonstrated by RT-PCR and Western blot. The content of GHRH protein in PC-3 xenografts was lowered markedly, by 66.3% ( P < 0.01), after treatment with JMR-132. GHRH induced a significant increase in levels of ERK, but JMR-132 abolished this outcome. Our findings indicate that inhibition of PC-3 prostate cancer by JMR-132 involves inactivation of Akt and ERK. The inhibitory effect produced by GHRH antagonist can result in part from inactivation of the PI3K/Akt/mammalian target of rapamycin and Raf/MEK/ERK pathways and from the reduction in GHRH produced by cancer cells. Our findings support the role of GHRH as an autocrine growth factor in prostate cancer and suggest that antagonists of GHRH should be considered for further development as therapy for CRPC.

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Section: Discussionsupporting

confidence: 92%

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confidence: 99%

Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases

Rick

Schally

Szalontay

et al. 2012

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

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“…By virtue of their androgen dependence, LNCaP and MDA PCa AR C cell lines are useful models to investigate mechanisms underlying CR. In addition, these cell lines have been employed to investigate the efficacy of novel therapeutic compounds, such as the histone deacetylase inhibitor valproic acid and the GH-releasing hormone antagonist MZ-J-7-138 (Chou et al 2011, Stangelberger et al 2012. Interestingly, ARCaP cells, which were established from ascites fluid of the same patient as MDA PCa cells, form tumors with high incidence when injected s.c. or orthotopically into intact or castrated male nude mice (Zhau et al 1996).…”

Section: Cell Lines Established Directly From Pca Patient Tissuesmentioning

confidence: 99%

In vitro model systems to study androgen receptor signaling in prostate cancer

Sampson

Neuwirt

Puhr

et al. 2013

Endocrine-Related Cancer

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Prostate cancer (PCa) is one of the most common causes of male cancer-related death in Western nations. The cellular response to androgens is mediated via the androgen receptor (AR), a ligand-inducible transcription factor whose dysregulation plays a key role during PCa development and progression following androgen deprivation therapy, the current mainstay systemic treatment for advanced PCa. Thus, a better understanding of AR signaling and new strategies to abrogate AR activity are essential for improved therapeutic intervention. Consequently, a large number of experimental cell culture models have been established to facilitate in vitro investigations into the role of AR signaling in PCa development and progression. These different model systems mimic distinct stages of this heterogeneous disease and exhibit differences with respect to AR expression/status and androgen responsiveness. Technological advances have facilitated the development of in vitro systems that more closely reflect the physiological setting, for example via the use of three-dimensional coculture to study the interaction of prostate epithelial cells with the stroma, endothelium, immune system and tissue matrix environment. This review provides an overview of the most commonly used in vitro cell models currently available to study AR signaling with particular focus on their use in addressing key questions relating to the development and progression of PCa. It is hoped that the continued development of in vitro models will provide more biologically relevant platforms for mechanistic studies, drug discovery and design ensuring a more rapid transfer of knowledge from the laboratory to the clinic.

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“…Furthermore, p53 is essential for solid organ protection against radiation damage and for maintenance of genomic integrity [23,24]. The expression of wild-type p53 is already known to be upregulated in prostate cancer cells [25,26] as well as hyperplastic benign prostate tissue treated with GHRH antagonists. Furthermore, intact p53 function is essential for solid organ protection against radiation damage and may be organ specific.…”

Section: Discussionmentioning

confidence: 99%

Antagonists of growth hormone releasing hormone (GHRH) given before whole body radiation lead to modulation of radiation response and organ-specific changes in the expression of angiogenesis

et al. 2012

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Purpose This study seeks to determine if growth hormonereleasing hormone (GHRH) antagonist, JMR-132, increases survival when given before whole body radiation. Material and methods C3H mice were divided into 14 groups. The first 7 groups were given whole body radiation alone in the increasing doses of 7, 7.5, 8, 8.5, 9, 10, and 11 Gy, respectively. The other 7 groups received JMR-132 (10 μg/day s.c.) for 3 weeks then received the whole body radiation in increasing doses of 7, 7.5, 8, 8.5, 9, 10, and 11 Gy, respectively. The experiment lasted 35 days. Hazard ratios for survival were calculated for the addition of the GHRH antagonist as compared to radiation alone at the different dose levels. RT-PCR was performed to identify potential target genes. CD31 immunohistochemical staining identified the differences between average vessel count. Results Mice pretreated with JMR-132 showed a longer survival at lower radiation doses, the hazard ratios were 0.34 and 0.59 when the drug was given with doses of 7.5 and 8 Gy, respectively. A statistically significant higher hazard ratio of 3.48 and 4.22 was seen in mice when GHRH antagonist was added to doses of 10 and 11 Gy, respectively. Organ specific upregulation of several target genes such as Akt2, ATM, and Trp53 was seen with the GHRH antagonist. In the animals pretreated with JMR-132 the small intestine and the kidney showed higher average vessel count. Conclusion Pretreatment with GHRH antagonist JMR-132 protects at lower doses of radiation.

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Inhibitory effects of antagonists of growth hormone releasing hormone on experimental prostate cancers are associated with upregulation of wild‐type p53 and decrease in p21 and mutant p53 proteins

Abstract: Our findings indicate that the anti-proliferative effects of GHRH antagonist MZ-J-7-138 and LHRH antagonist Cetrorelix on prostate cancers involve p53 and p21 signaling.

Cited by 27 publications

References 50 publications

Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases

Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases

In vitro model systems to study androgen receptor signaling in prostate cancer

Antagonists of growth hormone releasing hormone (GHRH) given before whole body radiation lead to modulation of radiation response and organ-specific changes in the expression of angiogenesis

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