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Combination of IFN- and 5-Fluorouracil Induces Apoptosis through IFN-/ß Receptor in Human Hepatocellular Carcinoma Cells

Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan

Requests for reprints: Hiroaki Nagano, Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka E2, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3251; Fax: 81-6-6879-3259; E-mail: hnagano{at}surg2.med.osaka-u.ac.jp.

Purpose: Several studies showed the effectiveness of combination therapy with IFN- 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-/ß receptor (IFN-/ßR) 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-/ßR 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-/ßR and up-regulation of -phospho–signal transducer and activator of transcription 1, IFN regulatory factor-1 by combination therapy were observed in all cell lines. Furthermore, IFN-/type 2 IFN receptor long form–transfected HuH7 cells treated with combination therapy showed strong DNA fragmentation compared with nontransfected or transfected with IFN-- and 5-FU-treated HuH7.

Conclusions: Our results showed that combination of IFN- plus 5-FU strongly induced cell growth inhibition of human hepatocellular carcinoma cells and indicated that oneof the direct mechanisms of combination therapy may in part be attributable to alterations in induction of apoptosis through IFN-/ßR.

Key Words: IFN- • 5-FU • IFN-/ßR • HCC • apoptosis