A novel approach in the treatment of neuroendocrine gastrointestinal tumors: additive antiproliferative effects of interferon-gamma and meta-iodobenzylguanidine.
BACKGROUND
Therapeutic options to effectively inhibit growth and spread of neuroendocrine gastrointestinal tumors are still limited. As both meta-iodobenzylguanidine (MIBG) and interferon-gamma (IFNgamma) cause antineoplastic effects in neuroendocrine gastrointestinal tumor cells, we investigated the antiproliferative effects of the combination of IFNgamma and non-radiolabeled MIBG in neuroendocrine gut STC-1 and pancreatic carcinoid BON tumor cells.


RESULTS
IFNgamma receptors were expressed in both models. IFNgamma dose- and time-dependently inhibited the growth of both STC-1 and of BON tumor cells with IC50-values of 95 +/- 15 U/ml and 135 +/- 10 U/ml, respectively. Above 10 U/ml IFNgamma induced apoptosis-specific caspase-3 activity in a time-dependent manner in either cell line and caused a dose-dependent arrest in the S-phase of the cell cycle. Furthermore, IFNgamma induced cytotoxic effects in NE tumor cells. The NE tumor-targeted drug MIBG is selectively taken up via norepinephrine transporters, thereby specifically inhibiting growth in NE tumor cells. Intriguingly, IFNgamma treatment induced an upregulation of norepinephrine transporter expression in neuroendocrine tumors cells, as determined by semi-quantitative RT-PCR. Co-application of sub-IC50 concentrations of IFNgamma and MIBG led to additive growth inhibitory effects, which were mainly due to increased cytotoxicity and S-phase arrest of the cell cycle.


CONCLUSIONS
Our data show that IFNgamma exerts antiproliferative effects on neuroendocrine gastrointestinal tumor cells by inducing cell cycle arrest, apoptosis and cytotoxicity. The combination of IFNgamma with the NE tumor-targeted agent MIBG leads to effective growth control at reduced doses of either drug. Thus, the administration of IFNgamma alone and more so, in combination with MIBG, is a promising novel approach in the treatment of neuroendocrine gastrointestinal tumors.
Höpfner
Michael
M
Charité - Universitätsmedizin Berlin, Institut für Anatomie, 10115, Germany. michael.hoepfner@charite.de
Sutter
Andreas P
AP
Huether
Alexander
A
Ahnert-Hilger
Gudrun
G
Scherübl
Hans
H
D019797:3-Iodobenzylguanidine / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects*; D004357:Drug Synergism; D016193:G1 Phase / Q000187:drug effects; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017471:Receptors, Interferon; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase / Q000187:drug effects; D018709:Statistics, Nonparametric; D027981:Symporters; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation
D050484:Norepinephrine Plasma Membrane Transport Proteins; D017471:Receptors, Interferon; C493227:SLC6A2 protein, human; D027981:Symporters; C120411:interferon receptor, type II; D019797:3-Iodobenzylguanidine; D007371:Interferon-gamma; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases