IFN-B Is a Highly Potent Inhibitor of Gastroenteropancreatic Neuroendocrine Tumor Cell Growth In vitro

IFN-A controls hormone secretion and symptoms in human gastroenteropancreatic neuroendocrine tumors (GEP-NET) but it rarely induces a measurable tumor size reduction. The effect of other type I IFNs, e.g., IFN-B, has not been evaluated. We compared the antitumor effects of IFN-A and IFN-B in BON cells, a functioning human GEP-NET cell line. As determined by quantitative reverse transcription-PCR analysis and immunocytochemistry, BON cells expressed the active type I IFN receptor mRNA and protein (IFNAR-1 and IFNAR-2c subunits). After 3 and 6 days of treatment, IFN-B significantly inhibited BON cell growth in a timeand dose-dependent manner. IC50 and maximal inhibitory effect on day 6 were 8 IU/mL and 98%, respectively. In contrast, the effect of IFN-A resulted significantly in a less potent effect (IC50: 44 IU/mL, maximal inhibition: 26%). IFN-A induced only cell cycle arrest, with an accumulation of the cells in S phase. IFN-B, apart from a more potent delay in S-G2-M phase transit of the cell cycle, also induced a strong stimulation of apoptosis, evaluated by flow cytometry (Annexin V and 7-AAD) and measurement of the DNA fragmentation. Besides, only IFN-B severely suppressed chromogranin A levels in the medium from BON cells after 6 days of treatment. In conclusion, IFN-B is much more potent, compared with IFN-A, in its inhibitory effect on GEP-NET cell proliferation in vitro through the induction of apoptosis and cell cycle arrest. Further studies are required to establish whether IFN-B has comparable potent tumor growth inhibitory effects in vivo . (Cancer Res 2006; 66(1): 554-62)