Potentiation of mammary cancer inhibition by combination of antagonists of growth hormone-releasing hormone with docetaxel

Buchholz, Stefan; Schally, Andrew V.; Engel, Jörg B.; Hohla, Florian; Heinrich, Elmar; Koester, Frank; Varga, József; Halmos, Gábor

doi:10.1073/pnas.0610860104

Cited by 44 publications

(35 citation statements)

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“…In previous breast cancer studies independent of the receptor status an inhibition of proliferation was observed, for example, in T47D estrogen receptor positive breast cancer cells by a GHRH antagonist in vitro [29] and in MXT mouse mammary cancer in vivo [16]. In a recent study we could show that in human estrogen receptor negative MX-1 breast cancers GHRH antagonists lead to marked inhibition of tumor growth in a nude mice model [42]. It was also demonstrated in this model, that co-treatment with a GHRH antagonist potentiated the antitumor effect of docetaxel [42], suggesting that GHRH antagonists are suitable partners for conventional chemotherapy.…”

Section: Discussionmentioning

confidence: 88%

“…In a recent study we could show that in human estrogen receptor negative MX-1 breast cancers GHRH antagonists lead to marked inhibition of tumor growth in a nude mice model [42]. It was also demonstrated in this model, that co-treatment with a GHRH antagonist potentiated the antitumor effect of docetaxel [42], suggesting that GHRH antagonists are suitable partners for conventional chemotherapy.…”

Section: Discussionmentioning

confidence: 91%

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Triple-negative breast cancers express receptors for growth hormone-releasing hormone (GHRH) and respond to GHRH antagonists with growth inhibition

Köster

Engel

Schally

et al. 2008

Breast Cancer Res Treat

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 91%

Triple-negative breast cancers express receptors for growth hormone-releasing hormone (GHRH) and respond to GHRH antagonists with growth inhibition

Köster

Engel

Schally

et al. 2008

Breast Cancer Res Treat

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“…As a proof of concept hGHRH analogs, JI-34 and JI-36, were able to induce a rise in intracellular calcium. In the same line, the selective hGHRH-R antagonists, JV-1-42 and JMR-132 (23)(24)(25)(26), behave as antagonists of the ghrelin receptor GHS-R1a. Finally, and quite remarkably, GHRH activated the endocytosis of the ghrelin receptor.…”

Section: Discussionmentioning

confidence: 94%

Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a

Casanueva

Camiña

Carreira

et al. 2008

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

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Ghrelin synergizes with growth hormone-releasing hormone (GHRH) to potentiate growth hormone (GH) response through a mechanism not yet fully characterized. This study was conducted to analyze the role of GHRH as a potential ligand of the ghrelin receptor, GHS-R1a. The results show that hGHRH(1-29)NH 2 (GHRH) induces a dose-dependent calcium mobilization in HEK 293 cells stably transfected with GHS-R1a an effect not observed in wildtype HEK 293 cells. This calcium rise is also observed using the GHRH receptor agonists JI-34 and JI-36. Radioligand binding and cross-linking studies revealed that calcium response to GHRH is mediated by the ghrelin receptor GHS-R1a. GHRH activates the signaling route of inositol phosphate and potentiates the maximal response to ghrelin measured in inositol phosphate turnover. The presence of GHRH increases the binding capacity of 125 I-ghrelin in a dose dependent-fashion showing a positive binding cooperativity. In addition, confocal microscopy in CHO cells transfected with GHS-R1a tagged with enhanced green fluorescent protein shows that GHRH activates the GHS-R1a endocytosis. Furthermore, the selective GHRH-R antagonists, JV-1-42 and JMR-132, act also as antagonists of the ghrelin receptor GHS-R1a. Our findings suggest that GHRH interacts with ghrelin receptor GHS-R1a, and, in consequence, modifies the ghrelin-associated intracellular signaling pathway. This interaction may represent a form of regulation, which could play a putative role in the physiology of GH regulation and appetite control.Ghrelin ͉ Ghrelin receptor ͉ GHRH T he recognition of ghrelin as the natural ligand for the growth hormone secretagogue receptor type 1a (GHS-R1a) added a new element to the complex physiological regulation for growth hormone (GH) secretion and clarified some of its aspects that were previously not fully understood (1, 2). However, this system is not as simple as it was initially thought. Ghrelin and its receptor became recognized not only for stimulating GH release but also for the findings that they exert an important role on several aspects of energy homeostasis and perhaps contribute to the metabolic syndrome (3, 4). One of the peculiar features of ghrelin and GH secretagogues (GHS) is the synergistic relationship with growth hormone-releasing hormone (GHRH) in the release of GH (5Ϫ7). The mechanism of this synergistic interaction remains a subject of debate in view of the fact that ghrelin and GHS act on both the hypothalamus and the pituitary. The evidence that this interaction requires a functional hypothalamus was obtained from patients with tumoral mass producing a hypothalamoϪpituitary disconnection in whom GH secretion is preserved after GHRH stimulation while GHS/ghrelin-induced GH secretion is blocked and the synergistic action between GHRH and GHS is absent (8, 9). Similar findings were observed in children with neonatal stalk transection (10). These observations led to the hypothesis that the action of ghrelin/GHS is mediated through an unknown hypothalamic factor with GHreleasi...

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“…Growth hormone-releasing hormone antagonists suppress the in vivo growth of various experimental cancers such as prostatic (Zarandi et al, 2006;Stangelberger et al, 2007), mammary (Buchholz et al, 2007), ovarian (Chatzistamou et al, 2001), renal cell carcinomas , small cell lung carcinomas (Hohla et al, 2006), pancreatic and colorectal carcinomas (Szepeshazi et al, 2000;Busto et al, 2002), endometrial (Engel et al, 2005), osteogenic sarcomas (Braczkowski et al, 2002) as well as malignant glioblastomas (Jaeger et al, 2005).…”

mentioning

confidence: 99%

Knocking down gene expression for growth hormone-releasing hormone inhibits proliferation of human cancer cell lines

Barabutis

Schally

2008

Br J Cancer

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Splice Variant 1 (SV-1) of growth hormone-releasing hormone (GHRH) receptor, found in a wide range of human cancers and established human cancer cell lines, is a functional receptor with ligand-dependent and independent activity. In the present study, we demonstrated by western blots the presence of the SV1 of GHRH receptor and the production of GHRH in MDA-MB-468, MDA-MB-435S and T47D human breast cancer cell lines, LNCaP prostate cancer cell line as well as in NCI H838 non-small cell lung carcinoma. We have also shown that GHRH produced in the conditioned media of these cell lines is biologically active. We then inhibited the intrinsic production of GHRH in these cancer cell lines using si-RNA, specially designed for human GHRH. The knocking down of the GHRH gene expression suppressed the proliferation of T47D, MDA-MB-435S, MDA-MB-468 breast cancer, LNCaP prostate cancer and NCI H838 non-SCLC cell lines in vitro. However, the replacement of the knocked down GHRH expression by exogenous GHRH (1 -29)NH 2 re-established the proliferation of the silenced cancer cell lines. Furthermore, the proliferation rate of untransfected cancer cell lines could be stimulated by GHRH (1 -29)NH 2 and inhibited by GHRH antagonists MZ-5-156, MZ-4-71 and JMR-132. These results extend previous findings on the critical function of GHRH in tumorigenesis and support the role of GHRH as a tumour growth factor.

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Potentiation of mammary cancer inhibition by combination of antagonists of growth hormone-releasing hormone with docetaxel

Abstract: breast cancer ͉ cancer therapy ͉ chemotherapeutic agents ͉ growth hormone-releasing hormone receptors

Cited by 44 publications

References 50 publications

Triple-negative breast cancers express receptors for growth hormone-releasing hormone (GHRH) and respond to GHRH antagonists with growth inhibition

Triple-negative breast cancers express receptors for growth hormone-releasing hormone (GHRH) and respond to GHRH antagonists with growth inhibition

Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a

Knocking down gene expression for growth hormone-releasing hormone inhibits proliferation of human cancer cell lines

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