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

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13 Scopus citations

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

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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

Rick, F. G., Seitz, S., Schally, A. V., Szalontay, L., Krishan, A., Datz, C., Stadlmayr, A., Buchholz, S., Block, N. L., & Hohla, F. (2012). GHRH antagonist when combined with cytotoxic agents induces S-phase arrest and additive growth inhibition of human colon cancer. Cell Cycle, 11(22), 4203-4210. https://doi.org/10.4161/cc.22498