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 K. Ganju-Krishan, Christian Datz, Andreas Stadlmayr, Stefan Buchholz, Norman L. Block, Florian Hohla

Research output: Contribution to journalArticle

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

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

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    Rick, F. G., Seitz, S., Schally, A. V., Szalontay, L., Ganju-Krishan, A. K., 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