Interferon alpha-2b and retinoic acid combined treatment affects proliferation and gene expression of human cervical carcinoma cells.

The in vivo and in vitro antitumor effectiveness of IFNs is well documented. Their combination with differentiating agents, such as retinoic acid, has been demonstrated to be a promising therapy for patients with advanced squamous cell cancer of the skin and the cervix. However, the mechanisms that mediate these antitumor responses are not yet known. We studied the epidermoid cell line ME 180 derived from human cervical carcinoma to test its responsiveness to IFN-alpha-2b (INTRON A) and all-trans-retinoic acid (RA). Both agents have demonstrated ability to inhibit the growth of ME 180 cells in a dose- and time-dependent manner. The antiproliferative effect was further increased by the treatment with IFN-alpha-2b and RA combined. In accordance with this result, we found that the combination of the two agents has the effect of increasing the expression of the 2-5A synthetase gene, which is thought to play a key role in antigrowth responses to IFNs. At increased levels of 2-5A synthetase mRNA corresponds a significant increase in 2-5A synthetase activity. Although RA per se has no effect on the 2-5A synthetase expression, when it is combined with IFN-alpha-2b it appears to be able to potentiate the IFN-induced 2-5A synthetase expression. Moreover, the combination of IFN-alpha-2b and RA produces a similar effect also on the expression of the HLA-A2 gene, which has been shown to be induced in ME 180 cells both by IFN-alpha-2b and RA alone. In view of the possible mechanisms of action of the two agents, it is interesting to note that their combination increases, although transiently, the expression of IRF1, which codes for a transcription factor that regulates IFN gene expression and is thought to be involved in the regulation of IFN-induced effects and in mediating cell death or apoptosis.