Combined effects of interferon-alpha2a and 13-cis-retinoic acid on human melanoma cell growth and STAT protein expression.
We assessed the antiproliferative effects of human recombinant interferon-alpha2a (IFNalpha2a) and 13-cis-retinoic acid (13cis-RA) on two human melanoma cell lines (JR8 and M14). Both cell lines showed a very modest sensitivity to IFNalpha2a 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 IFNalpha2a 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 IFNalpha2a markedly increased the nuclear expression of signal transducers and activators of transcription (STAT) proteins in both cell lines. By itself 10 microM 13cis-RA did not affect STAT protein expression or modify the extent of activation of such proteins by IFNalpha2a. Results from our study showed an enhancement of the antiproliferative activity of IFNalpha2a 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.
Bearzatto
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A
Divisione di Oncologia Sperimentale C, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.
Orlandi
L
L
Silvestrini
R
R
Belli
F
F
Cascinelli
N
N
Zaffaroni
N
N
D002452:Cell Count / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004338:Drug Combinations; D004357:Drug Synergism; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D015474:Isotretinoin / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D004338:Drug Combinations; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; D015534:Trans-Activators; D015474:Isotretinoin