Type I interferons in the treatment of pancreatic cancer: mechanisms of action and role of related receptors.
OBJECTIVE
We evaluated the role of type I interferons (IFNs) and IFN receptors in the regulation of cell growth in 3 human pancreatic adenocarcinoma cell lines (BxPC-3, MiaPaCa-2, and Panc-1).


BACKGROUND
Chemotherapy and radiotherapy have a marginal role in the management of pancreatic adenocarcinoma. The addition of IFN-alpha showed promising results in early clinical trials.


METHODS
Cell proliferation and apoptosis were evaluated by DNA measurement and DNA fragmentation, respectively. Type I IFN receptor (IFNAR-1 and IFNAR-2 subunits) was determined by quantitative RT-PCR and immunocytochemistry. Cell cycle distribution was evaluated by propidium iodide staining and flow-cytometric analysis.


RESULTS
The incubation with IFN-beta for 6 days showed a potent inhibitory effect on the proliferation of BxPC-3 (IC(50), 14 IU/mL) and MiaPaCa-2 (IC(50), 64 IU/mL). The inhibitory effect of IFN-beta was stronger than IFN-alpha in all 3 cell lines and mainly modulated by the stimulation of apoptosis, although cell cycle arrest was induced as well. The expression of the type I IFN receptors was significantly higher in BxPC-3 (the most sensitive cell line to IFN) and mainly localized on the membrane, whereas in Panc-1 (the most resistant cell line) about 60% to 70% of cells were negative for IFNAR-2c with a mainly cytoplasmic staining for IFNAR-2c.


CONCLUSIONS
The antitumor activity of IFN-beta is more potent than IFN-alpha in pancreatic cancer cell lines through the induction of apoptosis. Further studies should investigate in vivo whether the intensity and distribution of IFNAR-1 and IFNAR-2c may predict the response to therapy with IFN-alpha and IFN-beta in pancreatic cancer.
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Giovanni
G
Vitale
Casper H J
CH
van Eijck
Peter M
PM
van Koetsveld Ing
Joris I
JI
Erdmann
Ernst Jan M
EJ
Speel
Katy
K
van der Wansem Ing
Diana M
DM
Mooij
Annamaria
A
Colao
Gaetano
G
Lombardi
Ed
E
Croze
Steven W J
SW
Lamberts
Leo J
LJ
Hofland
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*; D053633:Receptor, Interferon alpha-beta / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; D007370:Interferon Type I; D012333:RNA, Messenger; D053633:Receptor, Interferon alpha-beta