TY - JOUR
T1 - Combination of IFN-α and 5-fluorouracil induces apoptosis through IFN-α/β receptor in human hepatocellular carcinoma cells
AU - Kondo, Motoi
AU - Nagano, Hiroaki
AU - Wada, Hiroshi
AU - Damdinsuren, Bazarragchaa
AU - Yamamoto, Hirofumi
AU - Hiraoka, Nobuaki
AU - Eguchi, Hidetoshi
AU - Miyamoto, Atsushi
AU - Yamamoto, Tameyoshi
AU - Ota, Hideo
AU - Nakamura, Masato
AU - Marubashi, Shigeru
AU - Dono, Keizo
AU - Umeshita, Koji
AU - Nakamori, Shoji
AU - Sakon, Masato
AU - Monden, Morito
PY - 2005/2/1
Y1 - 2005/2/1
N2 - Purpose: Several studies showed the effectiveness of combination therapy with IFN-α and 5-fluorouracil (5-FU) for advanced hepatocellular carcinoma. However, only little is known about the underlying mechanism of combination therapy. In the present study, we examined whether apoptosis through IFN-α/β receptor (IFN-α/βR) was associated with the effects of combination therapy. Experimental Design: HuH7, PLC/PRF/5, HLE, and HLF were treated with IFN- (500 units/mL), 5-FU (0.5 μg/mL), or their combination for 10 days. In addition, IFN-α/βR gene transfer with combination therapy was done. Results: Ten-day treatment by combination therapy resulted in >80% cell growth inhibition. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling analysis showed synergistic effects for combination therapy on PLC/PRF/5, HLE, and HLF. Concordant results were obtained with DNA fragmentation. Moreover, there was an evidence showing that changes in the expression of Bcl-2 family lead to apoptosis. On the other hand, the expression of IFN-α/βR and up-regulation of α-phospho- signal transducer and activator of transcription 1, IFN regulatory factor-1 by combination therapy were observed in all cell lines. Furthermore, IFN-α/type 2 IFN receptor long form-transfected HuH7 cells treated with combination therapy showed strong DNA fragmentation compared with non-transfected or transfected with IFN-α- and 5-FU-treated HuH7. Conclusions: Our results showed that combination of IFN-α plus 5-FU strongly induced cell growth inhibition of human hepatocellular carcinoma cells and indicated that one of the direct mechanisms of combination therapy may in part be attributable to alterations in induction of apoptosis through IFN-α/βR.
AB - Purpose: Several studies showed the effectiveness of combination therapy with IFN-α and 5-fluorouracil (5-FU) for advanced hepatocellular carcinoma. However, only little is known about the underlying mechanism of combination therapy. In the present study, we examined whether apoptosis through IFN-α/β receptor (IFN-α/βR) was associated with the effects of combination therapy. Experimental Design: HuH7, PLC/PRF/5, HLE, and HLF were treated with IFN- (500 units/mL), 5-FU (0.5 μg/mL), or their combination for 10 days. In addition, IFN-α/βR gene transfer with combination therapy was done. Results: Ten-day treatment by combination therapy resulted in >80% cell growth inhibition. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling analysis showed synergistic effects for combination therapy on PLC/PRF/5, HLE, and HLF. Concordant results were obtained with DNA fragmentation. Moreover, there was an evidence showing that changes in the expression of Bcl-2 family lead to apoptosis. On the other hand, the expression of IFN-α/βR and up-regulation of α-phospho- signal transducer and activator of transcription 1, IFN regulatory factor-1 by combination therapy were observed in all cell lines. Furthermore, IFN-α/type 2 IFN receptor long form-transfected HuH7 cells treated with combination therapy showed strong DNA fragmentation compared with non-transfected or transfected with IFN-α- and 5-FU-treated HuH7. Conclusions: Our results showed that combination of IFN-α plus 5-FU strongly induced cell growth inhibition of human hepatocellular carcinoma cells and indicated that one of the direct mechanisms of combination therapy may in part be attributable to alterations in induction of apoptosis through IFN-α/βR.
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M3 - Article
C2 - 15709199
AN - SCOPUS:19944430939
VL - 11
SP - 1277
EP - 1286
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 3
ER -