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

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.

• Authors: Ferenc G Rick, Stephan Seitz, Andrew V Schally, Luca Szalontay, Awtar Krishan, Christian Datz, Andreas Stadlmayr, Stefan Buchholz, Norman L Block, Florian Hohla
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 11 Issue 22 Pg. 4203-10 (Nov 15 2012) ISSN: 1551-4005 [Electronic] United States
• PMID: 23095641 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• GHRH(1-29)NH2, 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)-
• Irinotecan
• Sermorelin
• Growth Hormone-Releasing Hormone
• Cisplatin
• Fluorouracil
• Camptothecin

Topics

• Animals
• Antineoplastic Agents (therapeutic use, toxicity)
• Camptothecin (analogs & derivatives, therapeutic use, toxicity)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (therapeutic use, toxicity)
• Colonic Neoplasms (drug therapy, metabolism, pathology)
• Fluorouracil (therapeutic use, toxicity)
• Growth Hormone-Releasing Hormone (antagonists & inhibitors, metabolism)
• HCT116 Cells
• HT29 Cells
• Humans
• Irinotecan
• Mice
• Mice, Nude
• S Phase Cell Cycle Checkpoints (drug effects)
• Sermorelin (analogs & derivatives, therapeutic use, toxicity)
• Transplantation, Heterologous