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Partial Contribution of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)/TRAIL Receptor Pathway to Antitumor Effects of Interferon-/5-Fluorouracil against Hepatocellular Carcinoma

¹ Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka, University, Osaka, Japan; ² Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

Purpose: Our purpose was to explore the contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of IFN and 5-fluorouracil (5-FU) combination therapy for hepatocellular carcinoma (HCC).

Experimental Design: Susceptibility of HCC cell lines to TRAIL and/or 5-FU was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effects of 5-FU, IFN, or both on the expression of TRAIL receptors (R1, R2, R3, and R4) on HCC cells or TRAIL in peripheral blood mononuclear cells (PBMC) were examined by flow cytometry. IFN-induced cytotoxic effects of PBMC on HCC cell lines were examined by ⁵¹Cr release assay. TRAIL expression in peripheral blood mononuclear cells and liver tissue from patients was examined by real-time reverse transcription-PCR or immunohistochemistry.

Results: HLE and HepG2 were sensitive to TRAIL, but HuH7, PLC/PRF/5, and HLF were resistant. 5-FU had synergistic effect on TRAIL in HLF and additive effect in four other HCC cell lines. TRAIL receptors on HCC cells were up-regulated by 5-FU, and IFN induced TRAIL on CD4⁺ T cells, CD14⁺ monocytes, and CD56⁺ NK cells. Treatment of effector cells by IFN and target HCC cells by 5-FU enhanced the cytotoxicity of CD14⁺ monocytes and CD56⁺ NK cells against HCC cells via a TRAIL-mediated pathway. TRAIL mRNA overexpression was noted in PBMC of HCC patients who clinically responded to IFN/5-FU combination therapy, and TRAIL⁺ mononuclear cells were found in cancer tissue of a responder.

Conclusion: Our results suggest that modulation of TRAIL/TRAIL receptor-mediated cytotoxic pathway might partially contribute to the anti-HCC effect of IFN and 5-FU combination therapy.

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