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

Luca Szalontay, Andrew V Schally, Petra Popovics, Irving Vidaurre, Awtar Krishan, Marta Zarandi, Ren Zhi Cai, Anna Klukovits, Norman L Block, Ferenc G. Rick

Research output: Contribution to journalArticle

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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 μg/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 μM, and 19.2% at 5 μM, 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.

Original languageEnglish
Pages (from-to)2790-2797
Number of pages8
JournalCell Cycle
Volume13
Issue number17
DOIs
StatePublished - Sep 1 2014

Fingerprint

Hormone Antagonists
Growth Hormone-Releasing Hormone
Melanoma
Growth
Cell Cycle
Western Blotting
Cell Line
Neoplasms
G2 Phase
Skin Neoplasms
Heterografts
Nude Mice
Cell Division
Cell Count
Staining and Labeling
Drug Therapy

Keywords

  • Growth hormone-releasing hormone antagonist
  • Melanoma
  • P27
  • Targeted therapy
  • Xenografted mouse model

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Szalontay, L., Schally, A. V., Popovics, P., Vidaurre, I., Krishan, A., Zarandi, M., ... Rick, F. G. (2014). Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function. Cell Cycle, 13(17), 2790-2797. https://doi.org/10.4161/15384101.2015.945879

Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function. / Szalontay, Luca; Schally, Andrew V; Popovics, Petra; Vidaurre, Irving; Krishan, Awtar; Zarandi, Marta; Cai, Ren Zhi; Klukovits, Anna; Block, Norman L; Rick, Ferenc G.

In: Cell Cycle, Vol. 13, No. 17, 01.09.2014, p. 2790-2797.

Research output: Contribution to journalArticle

Szalontay, L, Schally, AV, Popovics, P, Vidaurre, I, Krishan, A, Zarandi, M, Cai, RZ, Klukovits, A, Block, NL & Rick, FG 2014, 'Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function', Cell Cycle, vol. 13, no. 17, pp. 2790-2797. https://doi.org/10.4161/15384101.2015.945879
Szalontay, Luca ; Schally, Andrew V ; Popovics, Petra ; Vidaurre, Irving ; Krishan, Awtar ; Zarandi, Marta ; Cai, Ren Zhi ; Klukovits, Anna ; Block, Norman L ; Rick, Ferenc G. / Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function. In: Cell Cycle. 2014 ; Vol. 13, No. 17. pp. 2790-2797.
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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 μg/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 μM, and 19.2{\%} at 5 μM, 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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