Novel antagonists of growth hormone‐releasing hormone inhibit growth and vascularization of human experimental ovarian cancers

Klinke, Anna; Schally, Andrew V.; Szalontay, Luca; Vidaurre, Irving; Papadia, Andrea; Zarándi, Márta; Varga, József; Block, Norman L.; Halmos, Gábor

doi:10.1002/cncr.26291

Cited by 31 publications

(33 citation statements)

References 65 publications

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“…This finding can further support the theories that, on certain cancer cells and tumors, SV1 functions as the main therapeutic target, 32 and in melanomas has a crucial role in the progression of the disease. 22 The exposure of A375 cells to MIA-690 altered the subcellular localization of p27, an event that is, at least in part, responsible for the observed changes in cell cycle progression.…”

Section: Discussionsupporting

confidence: 83%

“…41,42 In the present study, after treatment with MIA-690, the mRNA level of IL-8 markedly dropped. Our laboratory has earlier shown that treatment with GHRH-antagonists inhibits growth and vascularization of experimental ovarian cancer via decreasing VEGF secretion, 32 suggesting that one of the cornerstones of the antitumor effect of GHRH-antagonists might be derived from its angiogenesis inhibiting potential.…”

Section: Discussionmentioning

confidence: 99%

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Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function

et al. 2014

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Malignant melanoma is the deadliest form of skin cancer; the treatment of advanced and recurrent forms remains a challenge. It has recently been reported that growth hormone-releasing hormone (GHRH) receptor is involved in the pathogenesis of melanoma. Therefore, we investigated the effects of our new GHRH antagonists on a human melanoma cancer cell line. Antiproliferative effects of GHRH antagonists, MIA-602, MIA-606 and MIA-690, on the human melanoma cell line, A-375, were studied in vitro using the MTS assay. The effect of MIA-690 (5 mg/day 28 d) was further evaluated in vivo in nude mice bearing xenografts of A-375. Subcellular localization of p27 was detected with Western blot and immunofluorescent staining. MIA-690 inhibited the proliferation of A-375 cells in a dose-dependent manner (33% at 10 mM, and 19.2% at 5 mM, P < 0 .05 vs. control), and suppressed the growth of xenografted tumors by 70.45% (P < 0.05). Flow cytometric analysis of cell cycle effects following the administration of MIA-690 revealed a decrease in the number of cells in G2/M phase (from 19.7% to 12.9%, P < 0.001). Additionally, Western blot and immunofluorescent studies showed that exposure of A-375 cells to MIA-690 triggered the nuclear accumulation of p27. MIA-690 inhibited tumor growth in vitro and in vivo, and increased the translocation of p27 into the nucleus thus inhibiting progression of the cell cycle. Our findings indicate that patients with malignant melanoma could benefit from treatment regimens, which combine existing chemotherapy agents and novel GHRH-antagonists.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function

et al. 2014

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“…tumor growth in vivo, we obtained GHRH antagonists with greatly increased antitumor activity, but with reduced GH and IGF-1 inhibiting activity (6,22). Thus, the main effect of latest GHRH antagonists such as MIA-602 is likely to be exerted by the suppression of the action of tumoral GHRH through the inhibition of its binding to GHRH-Rs, which results in decreased cell cycle progression as well as increased apoptosis (6,13,21,50).…”

Section: Discussionmentioning

confidence: 98%

“…GHRH antagonists were prepared in our laboratory by solid-phase synthesis using Boc chemistry and purified by reversed-phase HPLC as described previously (6,22,25 ]hGH-RH(1-29)NH2. Noncoded amino acids and acyl groups used in the peptides are abbreviated as follows: Abu, α-aminobutyric acid; Ada, 12-aminododecanoic acid; Agm, agmatine; Cpa, parachloro-phenylalanine; Fpa5, pentafluoro-phenylalanine; Har, homoarginine; Me-Ala, Nmethyl-alanine; Nle, norleucine; Orn, ornithine; PhAc, phenylacetyl; Try (Me), O-methyl-tyrosine.…”

Section: Methodsmentioning

confidence: 99%

“…Unlike fulllength GHRH-R, SV1 displays ligand-independent activity in addition to ligand-dependent activity (17). Numerous investigations have examined the effects of GHRH antagonists on metastasis, invasion, and tumor growth in various cancer types (13,(18)(19)(20)(21)(22)(23)(24)(25)(26). Many of these published studies used early-stage GHRH antagonists that were later deemed unsuitable for clinical development owing to limited stability or low potency.…”

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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.

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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

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Early pregnancy IGF‐I and placental GH and risk of epithelial ovarian cancer: A nested case‐control study

Schöck

Fortner

Surcel

et al. 2014

Intl Journal of Cancer

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Insulin-like growth factor-I (IGF-I) signaling may promote ovarian tumor development by exerting mitotic, anti-apoptotic, and pro-angiogenic effects. During pregnancy, maternal production of IGF-I is regulated by placental growth hormone (GH). Parity is an established protective factor for ovarian cancer, however, no prior study has evaluated placental GH and IGF-I in pregnancy and epithelial ovarian cancer (EOC). Prior prospective studies on the association between IGF-I and EOC in non-pregnant populations were inconclusive and did not address associations in subtypes of EOC. Among members of the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort we identified 1,045 EOC cases, diagnosed after recruitment (1975-2008) and before March 2011, and 2,658 individually matched controls. Placental GH and IGF-I were measured in serum from the last pregnancy before EOC diagnosis or selection as control. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals [CI] for tertiles and a doubling of hormone concentrations. Higher IGFI was associated with a non-significant decrease in risk for invasive (ORT3 vs. T1: 0.79 [0.62-1.02]; ptrend=0.07) and endometrioid tumors (ORT3 vs. T1: 0.55 [0.28-1.07]; ptrend=0.07). The protective association between higher IGF-I levels and risk of invasive EOC was stronger in analyses limited to women aged <55 years at diagnosis (ORT3 vs. T1: 0.74 [0.57-0.96]; ptrend=0.03). Our study provides the first data on placental GH and IGF-I in pregnancy and EOC risk overall and by subtype. Our data suggest higher IGF-I levels in pregnancy may be associated with lower risk of invasive and endometrioid EOC.

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Novel antagonists of growth hormone‐releasing hormone inhibit growth and vascularization of human experimental ovarian cancers

Cited by 31 publications

References 65 publications

Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function

Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function

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

Early pregnancy IGF‐I and placental GH and risk of epithelial ovarian cancer: A nested case‐control study

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