Annals of Surgical Oncology

, 10:1184 | Cite as

Interferon-β Is More Potent Than Interferon-α in Inhibition of Human Hepatocellular Carcinoma Cell Growth When Used Alone and in Combination With Anticancer Drugs

  • Bazarragchaa Damdinsuren
  • Hiroaki Nagano
  • Masato Sakon
  • Motoi Kondo
  • Tameyoshi Yamamoto
  • Koji Umeshita
  • Keizo Dono
  • Shoji Nakamori
  • Morito Monden
Original Articles


Background:The prognosis of advanced hepatocellular carcinoma (HCC) is extremely poor, but promising effects of chemotherapies combined with interferon (IFN) have been reported.

Methods:To develop more effective combination therapies for HCC, we compared the antiproliferative effects of IFN-α and IFN-β in combination with various cytotoxic drugs on hepatoma cell lines using MTT assay and isobologram analysis.

Results:IFN-β was more potent than IFN-α in inhibiting the cell growth of all cell lines (P < .05, two-way ANOVA). PLC/PRF/5 was more sensitive to either IFN, than HLE and HuH7. Cell growth of all cell lines was inhibited in a dose-dependent manner by 5-fluorouracil (5-FU), cisplatin (CDDP), and doxorubicin (DOX), but the sensitivities of these cells were considerably different. As for IFN-α, synergistic effects were observed when combined with 5-FU and DOX on PLC/PRF/5 cells only, whereas IFN-β showed synergistic effects with 5-FU and CDDP on HuH7 and PLC/PRF/5 cell lines.

Conclusion:The spectra of the antiproliferative activity and synergistic effect of IFN-β when combined with anticancer drugs are more potent than those of IFN-α. Combinations of IFN-β and anticancer drugs may provide a better treatment of HCC when combinations with IFN-α are ineffective.

Key Words

Interferon Anticancer drug Cell proliferation HCC Combination therapy 


  1. 1.
    Okuda K. Hepatocellular carcinoma. J Hepatol 2000; 32 (suppl 1): 225–37.PubMedCrossRefGoogle Scholar
  2. 2.
    Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Seminin Liver Dis 1999; 19: 271–85.CrossRefGoogle Scholar
  3. 3.
    Anthony PP. Hepatocellular carcinoma: an overview. Histopathology 2001; 39: 109–18.PubMedCrossRefGoogle Scholar
  4. 4.
    Teo EK, Fock KM. Hepatocellular carcinoma: an Asian perspective. Dig Dis 2001; 19: 263–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Johnson PJ. Hepatocellular carcinoma: is current therapy really altering outcome? Gut 2002; 51: 459–62.PubMedCrossRefGoogle Scholar
  6. 6.
    Leung TW, Tang AM, Zee B, et al. Factors predicting response and survival in 149 patients with unresectable hepatocellular carcinoma treated by combination cisplatin, interferon-α, doxorubicin and 5-fluorouracil chemotherapy. Cancer 2002; 94: 421–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Urabe T, Kaneko S, Matsushita E, Unoura M, Kobayashi K. Clinical pilot study of intrahepatic arterial chemotherapy with methotrexate, 5-fluorouracil, cisplatin and subcutaneous interferon-α-2b for patients with locally advanced hepatocellular carcinoma. Oncology 1998; 55: 39–47.PubMedCrossRefGoogle Scholar
  8. 8.
    Sakon M, Nagano H, Dono K, et al. Combined intraarterial 5-fluorouracil and subcutaneous interferon-α therapy for advanced hepatocellular carcinoma with tumor thrombi in the major portal branches. Cancer 2002; 94: 435–42.PubMedCrossRefGoogle Scholar
  9. 9.
    Stuart K, Tessitore J, Huberman M. 5-Fluorouracil and α-interferon in hepatocellular carcinoma. Am J Clin Oncol 1996; 19: 136–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu Rev Biochem 1998; 67: 227–64.PubMedCrossRefGoogle Scholar
  11. 11.
    Berenbaum MC. Criteria for analyzing interactions between biologically active agents. Adv Cancer Res 1981; 35: 269–335.PubMedCrossRefGoogle Scholar
  12. 12.
    Von Hoff DD, Casper J, Bradley E, Sandbach J, Jones D, Makuch R. Association between human tumor colony-forming assay results and response of an individual patient’s tumor to chemotherapy. Am J Med 1981; 70: 1027–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Horikoshi T, Fukuzawa K, Hanada N, et al. In vitro comparative study of the antitumor effects of human interferon-α, β and γ on the growth and invasive potential of human melanoma cells. J Dermatol 1995; 22: 631–6.PubMedGoogle Scholar
  14. 14.
    Giandomenico V, Vaccari G, Fiorucci G, et al. Apoptosis and growth inhibition of squamous carcinoma cells treated with interferon-α, IFN-β and retinoic acid are associated with induction of the cyclin-dependent kinase inhibitor p21. Eur Cytokine Netw 1998; 9: 619–31.PubMedGoogle Scholar
  15. 15.
    Coradini D, Biffi A, Pirronello E, Di Fronzo G. The effect of α-, β- and γ-interferon on the growth of breast cancer cell lines. Anticancer Res 1994; 14: 1779–84.PubMedGoogle Scholar
  16. 16.
    Shen H, Zhang M, Minuk GY, Gong Y. Different effects of rat interferon α, β and γ on rat hepatic stellate cell proliferation and activation. BMC Cell Biol 2002; 3: 9–16.PubMedCrossRefGoogle Scholar
  17. 17.
    Platanias LC, Uddin S, Domanski P, Colamonici OR. Differences in interferon alpha and beta signaling. Interferon beta selectively induces the interaction of the α and βL subunits of the type I interferon receptor. J Biol Chem 1996; 271: 23630–3.PubMedCrossRefGoogle Scholar
  18. 18.
    Russell-Harde D, Wagner TC, Perez HD, Croze E. Formation of a uniquely stable type I interferon receptor complex by interferon beta is dependent upon particular interactions between interferon beta and its receptor and independent of tyrosine phosphorylation. Biochem Biophys Res Commun 1999; 255: 539–44.PubMedCrossRefGoogle Scholar
  19. 19.
    Chawla-Sarkar M, Leaman DW, Borden EC. Preferential induction of apoptosis by interferon (IFN)-beta compared with IFN-α2: correlation with TRAIL/Apo2L induction in melanoma cell lines. Clin Cancer Res 2001; 7: 1821–31.PubMedGoogle Scholar
  20. 20.
    Qin XQ, Runkel L, Deck C, DeDios C, Barsoum J. Interferon-beta induces S phase accumulation selectively in human transformed cells. J Interferon Cytokine Res 1997; 17: 355–67.PubMedCrossRefGoogle Scholar
  21. 21.
    Sangfelt O, Strander H. Apoptosis and cell growth inhibition as antitumor effector functions of interferons. Med Oncol 2001; 18: 3–14.PubMedCrossRefGoogle Scholar
  22. 22.
    Jonasch E, Haluska FG. Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist 2001; 6: 34–55.PubMedCrossRefGoogle Scholar
  23. 23.
    Kreuser ED, Wadler S, Thiel E. Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology. Recent Results Cancer Res 1995; 139: 371–82.PubMedGoogle Scholar
  24. 24.
    Makower D, Wadler S. Interferons as biomodulators of fluoropyrimidines in the treatment of colorectal cancer. Seminin Oncol 1999; 26: 663–71.Google Scholar
  25. 25.
    Eguchi H, Nagano H, Yamamoto H, et al. Augmentation of antitumor activity of 5-fluorouracil by interferon alpha is associated with up-regulation of p27Kip1 in human hepatocellular carcinoma cells. Clin Cancer Res 2000; 6: 2881–90.PubMedGoogle Scholar
  26. 26.
    Kondo M, Nagano H, Sakon M, et al. Expression of interferon alpha/beta receptor in human hepatocellular carcinoma. Int J Oncol 2000; 17: 83–8.PubMedGoogle Scholar

Copyright information

© The Society of Surgical Oncology, Inc. 2003

Authors and Affiliations

  • Bazarragchaa Damdinsuren
    • 1
  • Hiroaki Nagano
    • 1
  • Masato Sakon
    • 1
    • 2
  • Motoi Kondo
    • 1
  • Tameyoshi Yamamoto
    • 1
  • Koji Umeshita
    • 1
  • Keizo Dono
    • 1
  • Shoji Nakamori
    • 1
  • Morito Monden
    • 1
  1. 1.Department of Surgery and Clinical Oncology (E2)Graduate School of Medicine, Osaka UniversityOsakaJapan
  2. 2.Department of Surgery and Clinical Oncology (E2)Graduate School of Medicine, Osaka UniversityOsakaJapan

Personalised recommendations