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

Abstract

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.

Inhibition of experimental small‐cell and non‐small‐cell lung cancers by novel antagonists of growth hormone‐releasing hormone

“…MIA602 and MIA690 belong to the latest MIAMI series of potent GHRH antagonists with high antitumor activity on various cancers . In this study, we evaluated systematically the inhibitory effects of MIA602 and MIA690 on both SCLC and NSCLC in vitro and in vivo .…”

Antagonists of growth hormone-releasing hormone receptor induce apoptosis specifically in retinoblastoma cells

“…As GHRH-R is highly expressed in Y79 cells, we hypothesized that interfering with the GHRH signaling pathway would affect the cell cycle of the RB cells. We therefore treated these cells with 5 μM of the GHRH-R agonist MR-409, which reportedly enhanced the GHRH signaling pathway (13), for 24 or 48 h. These cells were also treated separately with similar concentration of GHRH-R antagonists MIA-602 or MIA-690, which suppressed the GHRH signaling pathway (14). There was no significant difference in the cell cycle stages at G1, S, and G2 between the solvent control and MR-409-, MIA-602-, or MIA-690-treated cells (Fig.…”

“…The GHRH-R agonist MR-409 and GHRH-R antagonists MIA-602 and MIA-690 were synthesized and purified as described previously (13,14) in the laboratory of A.V.S. The lyophilized synthetic neuropeptides were dissolved in 50% (vol/vol) acetic acid and then diluted 1,000-fold in corresponding culture medium before use.…”

“…GH expressions in the retina, indicating a role of GHRH-R antagonists in modulating functions in the retina at normal and pathological states (12). Notably, GHRH-R antagonists have been shown to trigger apoptosis and reduce the invasive and metastatic potential in late stage tumors, including glioblastoma, prostate, breast, and ovarian cancer (13,14). We therefore hypothesized that GHRH-R antagonists can induce cell death specifically in RB cells.…”

Potentiating effects of GHRH analogs on the response to chemotherapy

“…Other studies documented the expression of the pituitary type of receptors for GHRH (pGHRHR) as well as their splice variants (SVs), their wide distribution in most human cancers or cancer cell lines, and the inhibitory effects of GHRH receptor antagonists on the in vitro and in vivo growth of experimental human cancers. [1][2][3][4][5][6][7][8][9][10][11] The synthesis of GHRH antagonists was initiated because we postulated that they might be superior to potent octapeptide analogs of somatostatin which did not display adequate clinical efficacy (antitumor effects) in clinical trials on prostatic, mammary, colorectal and lung cancers or other cancers. 1 Our hypothesis that GHRH, in addition to its nominative function to control the release of GH from the pituitary, plays a major role as a tumor growth factor was inculpated by the fact that this neurohormone was obtained from pancreatic cancers, which produced enormous quantities of GHRH as compared to hypothalamic tissue.…”