Enhancement by Retinoic Acid and Dibutyryl Cyclic Adenosine 3′:5′-Monophosphate of the Differentiation and Gene Expression of Human Neuroblastoma Cells Induced by Interferon

Human neuroblastoma cell lines are induced to differentiate and display neuronal phenotypes when treated with interferon (IFN)-a2, retinoic acid (RA), or dibutyryl cyclic AMP (dbcAMP). We investigated the effects of combinations of these agents in induction-differentiation in the neuroblastoma cell line, NUB-6. The inductive effect of IFN-αwas markedly enhanced when used in combination with RA or dbcAMP. In parallel, RA or dbcAMP also enhanced the level of 2′-5′-oligoadenylate (2–5A) synthetase, an enzyme induced by IFNs and implicated in their biological action. The levels of another IFN-inducible enzyme, p68 kinase, were not enhanced by the combination treatments. The enhancement effects appeared to be exerted largely at the posttranscriptional level as both RA and dbcAMP stabilized IFN-induced 2–5A synthetase mRNA, resulting in increased enzyme activity. Thus, the 2–5A synthetase system is likely involved in mediating the IFN-α-induced differentiation of neuroblastoma cells and may also mediate the enhancement effects of RA and dbcAMP on IFN activity in these cells. These results also provide a rational basis for establishing a combination therapeutic approach for the treatment of neuroblastoma.