Abstract
BackgroundTherapeutic options to effectively inhibit growth and spread of neuroendocrine gastrointestinal tumors are still limited. As both meta-iodobenzylguanidine (MIBG) and interferon-γ (IFNγ) cause antineoplastic effects in neuroendocrine gastrointestinal tumor cells, we investigated the antiproliferative effects of the combination of IFNγ and non-radiolabeled MIBG in neuroendocrine gut STC-1 and pancreatic carcinoid BON tumor cells.Methods and resultsIFNγ receptors were expressed in both models. IFNγ 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 IFNγ 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, IFNγ 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, IFNγ 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 IFNγ and MIBG led to additive growth inhibitory effects, which were mainly due to increased cytotoxicity and S-phase arrest of the cell cycle.ConclusionOur data show that IFNγ exerts antiproliferative effects on neuroendocrine gastrointestinal tumor cells by inducing cell cycle arrest, apoptosis and cytotoxicity. The combination of IFNγ with the NE tumor-targeted agent MIBG leads to effective growth control at reduced doses of either drug. Thus, the administration of IFNγ alone and more so, in combination with MIBG, is a promising novel approach in the treatment of neuroendocrine gastrointestinal tumors.
Highlights
Therapeutic options to effectively inhibit growth and spread of neuroendocrine gastrointestinal tumors are still limited. As both meta-iodobenzylguanidine (MIBG) and interferonγ (IFNγ) cause antineoplastic effects in neuroendocrine gastrointestinal tumor cells, we investigated the antiproliferative effects of the combination of IFNγ and non-radiolabeled MIBG in neuroendocrine gut STC-1 and pancreatic carcinoid BON tumor cells
EgFaxisgptureorseinsit1oenstoinfaIlFtNumγ roercceepltlos rs (IFNγR) in neuroendocrine Expression of IFNγ receptors (IFNγR) in neuroendocrine gastrointestinal tumor cells. mRNA expression of IFNγR was evaluated in human pancreatic carcinoid BON tumor cells
Additive antiproliferative effects of IFNγ and MIBG Recently, we showed that non-radiolabeled MIBG inhibited the growth of norepinephrine transporter (NET)-expressing STC-1 tumor cells (IC50 ~ 8 μM) and that MIBG-treatment increased the expression of IFNγ receptors
Summary
Therapeutic options to effectively inhibit growth and spread of neuroendocrine gastrointestinal tumors are still limited. As both meta-iodobenzylguanidine (MIBG) and interferonγ (IFNγ) cause antineoplastic effects in neuroendocrine gastrointestinal tumor cells, we investigated the antiproliferative effects of the combination of IFNγ and non-radiolabeled MIBG in neuroendocrine gut STC-1 and pancreatic carcinoid BON tumor cells. A promising approach for novel treatment of NE gastrointestinal tumor disease may be the modulation of the IFNγreceptor system. IFNγ-induced STAT signaling and STAT-associated induction of interferon regulatory factors (IRFs) have been shown to exert key regulatory function for proliferation, differentiation and survival [4]. The underlying mechanisms of IFNγ-induced growth inhibition show a broad spectrum, including the induction of cell cycle arrest, apoptosis and cytotoxcicity [5,6]
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