GHRH antagonist when combined with cytotoxic agents induces S-phase arrest and additive growth inhibition of human colon cancer

Ferenc G. Rick, Stephan Seitz, Andrew V Schally, Luca Szalontay, Awtar Krishan, Christian Datz, Andreas Stadlmayr, Stefan Buchholz, Norman L Block, Florian Hohla

Research output: Contribution to journalArticle

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Abstract

Treatment of colon cancer with an antagonist of growth hormone-releasing hormone (GHRH), JMR-132, results in a cell cycle arrest in S-phase of the tumor cells. Thus, we investigated the effect of JMR-132 in combination with S-phase-specific cytotoxic agents, 5-FU, irinotecan and cisplatin on the in vitro and in vivo growth of HT-29, HCT-116 and HCT-15 human colon cancer cell lines. In vitro, every compound inhibited proliferation of HCT-116 cells in a dose-dependent manner. Treatment with JMR-132 (5 μM) combined with 5-FU (1.25 μM), irinotecan (1.25 μM) or cisplatin (1.25 μM) resulted in an additive growth inhibition of HCT-116 cells in vitro as shown by MTS assay. Cell cycle analyses revealed that treatment of HCT-116 cells with JMR-132 was accompanied by a cell cycle arrest in S-phase. Combination treatment using JMR-132 plus a cytotoxic drug led to a significant increase of the sub-G 1 fraction, suggesting apoptosis. In vivo, daily treatment with GHRH antagonist JMR-132 decreased the tumor volume by 40-55% (p < 0.001) of HT-29, HCT-116 and HCT-15 tumors xenografted into athymic nude mice. Combined treatment with JMR-132 plus chemotherapeutic agents 5-FU, irinotecan or cisplatin resulted in an additive tumor growth suppression of HT-29, HCT-116 and HCT-15 xenografts to 56-85%. Our observations indicate that JMR-132 enhances the antiproliferative effect of S-phase-specific cytotoxic drugs by causing accumulation of tumor cells in S-phase.

Original languageEnglish
Pages (from-to)4203-4210
Number of pages8
JournalCell Cycle
Volume11
Issue number22
DOIs
StatePublished - Nov 15 2012

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Hormone Antagonists
Growth Hormone-Releasing Hormone
Cytotoxins
S Phase
Colonic Neoplasms
irinotecan
Growth
HCT116 Cells
Fluorouracil
Cisplatin
Cell Cycle Checkpoints
Nude Mice
Neoplasms
PhAcTyr(1)-Arg(2)-P(H)e(4-CL)(6)-Ala(8)-Tyr(Me)(10)-His(11)-Abu(15)-His(20)-Nle(27)-Arg(28)-HLCr(29)-gHRH(1-29)NH2
Tumor Burden
Heterografts
Pharmaceutical Preparations
Cell Cycle
Apoptosis
Cell Line

Keywords

  • Additive growth inhibition
  • Colon cancer
  • Cytotoxic agents
  • GHRH antagonist
  • JMR-132
  • S-phase arrest
  • Targeted therapy

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

GHRH antagonist when combined with cytotoxic agents induces S-phase arrest and additive growth inhibition of human colon cancer. / Rick, Ferenc G.; Seitz, Stephan; Schally, Andrew V; Szalontay, Luca; Krishan, Awtar; Datz, Christian; Stadlmayr, Andreas; Buchholz, Stefan; Block, Norman L; Hohla, Florian.

In: Cell Cycle, Vol. 11, No. 22, 15.11.2012, p. 4203-4210.

Research output: Contribution to journalArticle

Rick, FG, Seitz, S, Schally, AV, Szalontay, L, Krishan, A, Datz, C, Stadlmayr, A, Buchholz, S, Block, NL & Hohla, F 2012, 'GHRH antagonist when combined with cytotoxic agents induces S-phase arrest and additive growth inhibition of human colon cancer', Cell Cycle, vol. 11, no. 22, pp. 4203-4210. https://doi.org/org/10.4161/cc.22498
Rick, Ferenc G. ; Seitz, Stephan ; Schally, Andrew V ; Szalontay, Luca ; Krishan, Awtar ; Datz, Christian ; Stadlmayr, Andreas ; Buchholz, Stefan ; Block, Norman L ; Hohla, Florian. / GHRH antagonist when combined with cytotoxic agents induces S-phase arrest and additive growth inhibition of human colon cancer. In: Cell Cycle. 2012 ; Vol. 11, No. 22. pp. 4203-4210.
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AU - Seitz, Stephan

AU - Schally, Andrew V

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AU - Krishan, Awtar

AU - Datz, Christian

AU - Stadlmayr, Andreas

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