Combined effects of interferon-α2a and 13-cis-retinoic acid on human melanoma cell growth and STAT protein expression

We assessed the antiproliferative effects of human recombinant interferon-alpha 2a (IFN alpha 2a) and 13-cis-retinoic acid (13 cis-RA) on two human melanoma cell lines (JR8 and M14). Both cell lines showed a very modest sensitivity to IFN alpha 2a and 13cis-RA as single agents. In JR8 cells, the combination of the two compounds consistently produced simple additive effects. In contrast, different effects of the combination were recorded in the M14 cell line depending on the treatment schedule. Specifically, an additive interaction was observed when IFN alpha 2a and 13cis-RA were given in sequence, independently of the order of drug administration, whereas a supra-additive antiproliferative effect was seen when cells were simultaneously exposed to the two drugs. Exposure to 1000 IU/ml IFN alpha 2a markedly increased the nuclear expression of signal transducers and activators of transcription (STAT) proteins in both cell lines. By itself 10 mu M 13cis-RA did not affect STAT protein expression or modify the extent of activation of such proteins by IFN alpha 2a. Results from our study showed an enhancement of the antiproliferative activity of IFN alpha 2a and 13cis-RA when given in combination and suggest that such an enhancement is not mediated by a concomitant effect of 13cis-RA on STAT protein activation. (C) 1998 Rapid Science Ltd.