Apoptosis and growth inhibition of squamous carcinoma cells treated with interferon-alpha, IFN-beta and retinoic acid are associated with induction of the cyclin-dependent kinase inhibitor p21.
Recent studies have revealed promising leads on the potential of interferons (IFNs) in combination with retinoids in solid tumor therapy. The role of IFN-alpha and retinoic acid (RA) in cervical cancer is currently under active study. Because preclinical and clinical data on IFN-beta in combination with retinoids show promising results against breast carcinoma, we analysed the anti-proliferative effect of human recombinant IFN-beta alone or in combination with all-trans RA on two human squamous cervical carcinoma cell (SCC) lines (ME180 and SiHa). The two cell lines differ in their sensitivity to the anti-proliferative effects of the different agents and their combination: i) both cell lines were more responsive to IFN-beta than to IFN-alpha2b; ii) combined treatment with RA increases the growth inhibitory effect of the single agents in ME180, but not in SiHa; iii) the antiproliferative effect correlates with the induction of apoptosis. We suggest as a possible mechanisms of action that interferon regulatory factor-1 (IRF-1), a transcription factor which belongs to the IFN machinery, and the cyclin-dependent kinase inhibitor (CDKi) p21 can be involved in cellular growth inhibition and in the induction of apoptosis. These results support the use of IFN-beta in further clinical investigation possibly in combination with retinoids.
Giandomenico
V
V
Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy.
Vaccari
G
G
Fiorucci
G
G
Percario
Z
Z
Vannuchi
S
S
Matarrese
P
P
Malorni
W
W
Romeo
G
G
Affabris
G R
GR
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D053938:DNA Fragmentation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050856:Interferon Regulatory Factor-1; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D016899:Interferon-beta / Q000008:administration & dosage / Q000627:therapeutic use*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D014212:Tretinoin / Q000008:administration & dosage / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D010750:Phosphoproteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014212:Tretinoin; D016899:Interferon-beta; D018844:Cyclin-Dependent Kinases; D015088:2',5'-Oligoadenylate Synthetase