Increased activity of antagonists of growth hormone-releasing hormone substituted at positions 8, 9, and 10

Varga, József; Schally, Andrew V.; Horváth, Judit; Kovács, Magdolna; Halmos, Gábor; Groot, Kate; Toller, Gabor L.; Rékási, Zoltán; Zarándi, Márta

doi:10.1073/pnas.0307288101

Cited by 44 publications

(55 citation statements)

References 27 publications

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“…In recent years several series of antagonistic analogs of growth hormone-releasing hormone (GHRH) were synthesized in an endeavour to develop a new class of antineoplastic agents [8][9][10][11]. GHRH antagonists inhibit the growth of various experimental human cancers [12], but their effects on triple-negative breast cancers have not been studied.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, it was observed that GHRH antagonists can inhibit the proliferation of diverse cancer lines by direct action in vitro, under conditions in which the contribution of the hypothalamic GHRH/pituitary GH/hepatic IGF-I axis is clearly excluded [8,[13][14][15][16][17][18][19][20][21][22][23][24][25]. These studies led to the conclusion that the main mechanism responsible for tumor inhibition could be a direct effect of the antagonists on the tumor tissue [8,11]. These findings may now be explained by recent discoveries regarding the role of tumoral GHRH and GHRH receptors in the proliferation of cancers.…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…SV-1 differs from the pituitary GHRH-R in a small portion of its amino-terminal region. Many antagonistic analogs of GHRH have been synthesized (2,5,7,8). These analogs inhibit tumor growth by blocking GH and hepatic secretion of insulinlike growth factor 1 (IGF-1), as well as by suppressing the synthesis of tumoral autocrine/paracrine IGF-1 and/or IGF-II (8)(9)(10)(11), and by blocking the effects of autocrine GHRH on tumors.…”

Section: Introductionmentioning

confidence: 99%

“…Growth hormone (GH)-releasing hormone (GHRH) is a 40-44 amino acid hypothalamic peptide that regulates the secretion of GH from the anterior pituitary gland (5). In addition to having neuroendocrine action, GHRH acts directly on a variety of peripheral tissues and tumors and induces cell proliferation (6).…”

Section: Introductionmentioning

confidence: 99%

The Immunohistochemical Expression of Growth Hormone-Releasing Hormone Receptor Splice Variant 1 Is a Favorable Prognostic Marker in Colorectal Cancer

Theophanous

Petraki

Scorilas

et al. 2009

Mol Med

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Hypothalamic growth hormone (GH)-releasing hormone (GHRH) regulates the release of GH from the pituitary gland. The receptors for GHRH (GHRH-R) are expressed predominantly in the pituitary. Recent evidence demonstrates that splice variants of the GHRH receptor are also expressed in several nonpituitary tissues, both normal and tumoral, as well as in cancer cell lines. The aim of this study was to investigate the expression of the splice variant 1 (SV-1) of GHRH-R in colorectal cancer (CRC). Seventy patients who underwent partial colectomy for CRC were enrolled in the study. Immunohistochemical expression of SV-1 was studied in paraffin-embedded sections of patient tumor tissue. A cytoplasmic supranuclear expression of SV-1 was observed in CRC as well as in the normal colon mucosa. Tumor grade and pathological stage were negatively correlated with expression of SV-1 (P = 0.012 and P = 0.013, respectively). CRCs metastatic to the liver showed a lower expression of SV-1 than did primary tumors, but this difference was not statistically significant. Kaplan-Meier and Cox univariate survival analyses indicated an improved survival time in patients with high SV-1 compared with those with low GHRH-R expression, but this difference was not statistically significant. The immunohistochemical expression of SV-1 seems to be a favorable prognostic factor in CRC.

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“…Thus, GHRH antagonists can suppress tumor growth indirectly by blocking GH release from the pituitary and consequently the hepatic production of IGF-I (6,12), which is an established mitogen for various cancers (13), is likewise inhibited. Nevertheless, GHRH antagonists, exert their main antitumor effects through direct mechanisms (12,14), by the inhibition of tumoral GHRH and IGF-I and/or IGF-II (6,(14)(15)(16), which serve as autocrine/paracrine growth factors. Pituitary-type GHRH receptors (pGHRH-R) and their splice variants (SVs) have been detected in different human cancers and various cancer cell lines (17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

The effect of a novel antagonist of growth hormone releasing hormone on cell proliferation and on the key cell signaling pathways in nine different breast cancer cell lines

et al. 2011

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Abstract. Growth hormone releasing hormone (GHRH) antagonists have been developed for the treatment of various cancers. We investigated the effects of a novel GHRH antagonist, MIA-602, on nine breast cancer cell lines, differing in their expression for estrogen-, progesterone-and HER-2 receptors. We detected the presence of pituitary-type GHRH receptors (pGHRH-R) on 6 of the 9 breast cancer cell lines. The main splice variant of pGHRH-R, SV1, was found on all 9 cell lines. MTT assay showed that following treatment with MIA-602, cell viability decreased significantly in all 9 cell lines. The reduction in cell viability was greater in cells positive for both pGHRH-R and SV1, than in cells positive for only SV1, but the difference was not significant. Using Western blotting, we demonstrated that the levels of phosphoAkt, -GSK3β and -ERK1/2 decreased significantly following exposure to MIA-602 and the level of phospho-p38 increased after treatment. The reduction of the phosphorylated antiapoptotic proteins was significantly greater in cells where both pGHRH-R and SV1 were present, than where only SV1 was expressed. In conclusion, our study shows that MIA-602 is effective against a wide range of breast cancer cells in vitro, independently of their receptor positivity, suggesting the potential use of GHRH antagonists also in the treatment of triple-negative breast cancer. The effect of MIA-602 was mediated nearly as well in tumors that expressed only the SV1 receptor compared to those in which both SV1 and pGHRH-R were present, although a difference could be detected at the level of cell signaling.

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Increased activity of antagonists of growth hormone-releasing hormone substituted at positions 8, 9, and 10

Cited by 44 publications

References 27 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

The Immunohistochemical Expression of Growth Hormone-Releasing Hormone Receptor Splice Variant 1 Is a Favorable Prognostic Marker in Colorectal Cancer

The effect of a novel antagonist of growth hormone releasing hormone on cell proliferation and on the key cell signaling pathways in nine different breast cancer cell lines

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