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Cancer Chemotherapy and Pharmacology

, Volume 35, Issue 1, pp 10–16 | Cite as

Positive interactions between human interferon and cepharanthin against human cancer cells in vitro and in vivo

  • Minoru Ono
  • Noriaki Tanaka
  • Kunzo Orita
Original Article Interferon, Cepharanthin, Antitumor Effect

Abstract

A human tumor microcytotoxicity-viable cell-staining assay was used to test the antiproliferative effect of recombinant human interferon-beta or-gamma alone and in combination with bisbenzylisoquinoline alkaloid cepharanthin against four human tumor cell lines in vitro and in nude mice. Results obtained in the in vitro study indicate that combinations of interferon-beta/gamma with cepharanthin show synergistic and, occasionally, additive antiproliferative effects in a dose-dependent manner on tumor viable cell-staining assay. Interferon-gamma combined with cepharanthin suppressed the growth of all four human tumor cell lines (RPMI 4788, PC 10, HeLa, ZR-75-1), and this enhanced antiproliferative effect was not dependent on the interferon species involved, including interferon-beta and-gamma. In an experimental model of pulmonary metastasis, in which human colon tumor cells were inoculated i.v. into nude mice, interferon-gamma alone exerted significant inhibitory activity against pulmonary metastasis in a dose-dependent manner, and cepharanthin alone also significantly inhibited metastasis. Furthermore, a combination of interferon-gamma with cepharanthin resulted in a considerable suppression of pulmonary metastasis. These studies indicate that due to their therapeutic potential, combinations of recombinant human interferon-beta or-gamma with cepharanthin might be a promising therapy for pulmonary metastasis of human cancers.

Key words

Interferon Cepharanthin Antitumor effect 

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References

  1. 1.
    Gresser I, Tovey M (1978) Antitumor effects of interferon. Biochim Biophys Acta 516:231–247Google Scholar
  2. 2.
    Merigan TC, Sikora K, Breeden JH, Lery R, Rosenburg SA (1978) Preliminary observation on the effect of human leukocyte interferon in non-Hodgkin's lymphoma. N Engl J Med 299: 1449–1453Google Scholar
  3. 3.
    Quesada JR, Swanson DA, Trindade A, Gutterman JU (1983) Renal cell carcinoma: antitumor effects of leukocyte interferon. Cancer Res 43:940–947Google Scholar
  4. 4.
    Taylor-Papadimitriou J, Balkwill FR (1982) Implications for clinical application of new developments in interferon research. Biochim Biophys Acta 695:49–67Google Scholar
  5. 5.
    Balkwill R, Moodie EM (1984) Positive interaction between human interferon and cyclophosphamide or adriamycin in a human tumor model system. Cancer Res 44:904–908Google Scholar
  6. 6.
    Heston WDW, Fleischmann J, Tackett RE, Ratliff TL (1984) Effects of α-difluoromethylornithine and recombinant interferon-α2 on the growth of a human renal cell adeno-carcinoma xenograft in nude mice. Cancer Res 44:3220–3225Google Scholar
  7. 7.
    Aapro MS, Alberts DS, Salmon SE (1983) Interaction of human leukocyte interferon with vinca alkaloids and other chemotherapeutic agents against human tumors in clonogenic assay. Cancer Chemother Pharmacol 10:161–166Google Scholar
  8. 8.
    Brostrom LA (1980) The combined effect of interferon and methotrexate on human osteosarcoma and lymphoma cell lines. Cancer Lett 10:83–90Google Scholar
  9. 9.
    Inoue M, Tan YH (1983) Enhancement of actinomycin D andcis-diaminedichloroplatinum(II)-induced killing of human fibroblasts by human β-interferon. Cancer Res 43:5484–5488Google Scholar
  10. 10.
    Yamamoto S, Tanaka H, Kanamori T, Nobuhara M, Namba M (1983) In vitro studies on potentiation of cytotoxic effects of anticancer drugs by interferon on a human neoplastic cell line (HeLa). Cancer Lett 20:131–138Google Scholar
  11. 11.
    Gutterman JU, Fien S, Quesada J, Horning SJ, Levine JF, Alexanian R, Bernhardt L, Kramer M, Spiegel H, Colburn W, Trown P, Merigan T, Dziewanowski Z (1982) Recombinant leukocyte A interferon: pharmacokinetics, single-dose tolerance, and biologic effects in cancer patients. Ann Intern Med 96:549–556Google Scholar
  12. 12.
    Hamburger AW, Salmon SE (1977) Primary bioassay of human tumor stem cells. Science 197:461–463Google Scholar
  13. 13.
    Havell EA, Vilcek J (1975) Inhibition of interferon secretion by vinblastine. J Cell Biol 64:716–719Google Scholar
  14. 14.
    Utsumi K, Miyahara M, Sugiyama K, Sasaki J (1976) Effect of biscoclaurine alkaloid on the cell membrane related to membrane fluidity. Acta Histochem Cytochem 9:59–68Google Scholar
  15. 15.
    Watanabe S (1984) Inhibition of platelet aggregation by cepharanthine is accomplished during the early membrane-related activation process. Acta Med Okayama 38:101–115Google Scholar
  16. 16.
    Kato T, Suzumura Y (1987) Potentiation of antitumor activity of vincristine by the biscoclaurine alkaloid cepharanthine. J Natl Cancer Inst 79:527–532Google Scholar
  17. 17.
    Nagaoka S, Kawasaki S, Karino Y, Sasaki K, Nakanishi T (1987) Modification of cellular efflux and cytotoxicity of adriamycin by biscoclaurine alkaloid in vitro. Eur J Clin Oncol 23:1297–1302Google Scholar
  18. 18.
    Miyahara M, Aono K, Queseda JS, Shimono K, Baba Y, Yamashita S (1987) Protection by cepharanthin of the mitochondrial function from damage induced by snake venom, phospholipase A2, lysolecithin and lead. Cell Struct Funct 3:61–65Google Scholar
  19. 19.
    Shiraishi N, Akiyama S, Nakagawa M, Kobayashi M, Kuwano M (1987) Effect of bisbenzylisoquinoline (biscoclaurine) alkaloids on multidrug resistance in KB human cancer cells. Cancer Res 47: 2413–2416Google Scholar
  20. 20.
    Shiraishi N, Shimada T, Hagino Y, Kohno K, Kobayashi M, Kuwano M, Akiyama S (1988) Potentiation by a biscoclaurine alkaloid, cepharanthine, of the toxicity of conjugates of epidermal growth factor withPseudomonas exotoxin in HeLa cells. Cancer Res 48:1307–1311Google Scholar
  21. 21.
    Ono M (1987) Antitumor effect of cepharanthin: activation of regional lymph node lymphocytes by intratumoral administration. Clin Immunol 19:1061–1064Google Scholar
  22. 22.
    Morioka S, Ono M, Tanaka N, Orita K (1985) Synergistic activation of rat alveolar macrophages by cepharanthin and OK-432. Jpn J Cancer Chemother 12:1470–1475Google Scholar
  23. 23.
    Moore GE, Koike A (1964) Growth of human tumor cells in vitro and in vivo. Cancer 17:11–20Google Scholar
  24. 24.
    Inoue S, Ito M, Mizuno S, Isobe H, Miyamoto H, Kawakami Y, Ohnuma T (1988) Simultaneous flow cytometric detection of nuclear DNA and tumor-associated antigens in lung cancers. Anal Quant Cytol Histol 10:243–250Google Scholar
  25. 25.
    Gey GO, Coffman WD, Kubicek MT (1952) Tissue culture studies of the proliferative capacity of cervical carcinoma and normal epithelium. Cancer Res 12:264Google Scholar
  26. 26.
    Engel LW, Young NA, Tralka TS, Lippman NE, O'Brien SJ, Joyce MJ (1978) Establishment and characterization of three new continuous cell lines derived from human breast carcinomas. Cancer Res 38:3352–3364Google Scholar
  27. 27.
    Gomi K, Morimoto M, Nakamizo N (1983) Growth-inhibitory activity of recombinant human interferon-β against cultured human cells. Jpn J Cancer Res 74:737–742Google Scholar
  28. 28.
    Shimada Y, Shimoyama M (1984) Growth-inhibitory activity of human recombinant β-interferon (GKT-β) in vitro. Jpn J Cancer Res 75:1116–1124Google Scholar
  29. 29.
    Gomi K, Morimoto M, Nakamizo N (1985) Characteristics of antiviral and anticellular activities of human recombinant interferon-γ. Jpn J Cancer Res 76:224–234Google Scholar
  30. 30.
    Takasugi M, Klein E (1971) The methodology of microassay for cell-mediated immunity. In: Bloom BR, Glade PR (eds) In vitro methods in cell-mediated immunity. Academic Press, New York, p 415Google Scholar
  31. 31.
    Lee SH, Aggarwal BB, Rinderknecht E, Assisi F, Chiu H (1984) The synergistic antiproliferative effect of γ-interferon and human lymphotoxin. J Immunol 133:1083–1086Google Scholar
  32. 32.
    Reference deletedGoogle Scholar
  33. 33.
    Oku T, Imanishi J, Kishida T (1982) Assessment of antitumor cell effect of human leukocyte interferon in combination with anticancer agents by a convonient assay system in monolayer cell culture. Jpn J Cancer Res 73:667–674Google Scholar
  34. 34.
    Naomoto Y, Kondo H, Tanaka N, Orita K (1987) Novel experimental models of human cancer metastasis in nude mice: lung metastasis, intraabdominal carcinomatosis with ascites, and liver metastasis. J Cancer Res Clin Oncol 113:544–549Google Scholar
  35. 35.
    Wexler HMA (1966) Accurate identification of experimental pulmonary metastasis. J Natl Cancer Inst 36:641–645Google Scholar
  36. 36.
    Kubota R, Kubota K, Yamada S (1992) Enhancement of the effects of anticancer agents on B16 melanoma cells by combination with cepharanthine. I. Alkaloids. Jpn J Cancer Chemother 19: 2163–2167Google Scholar
  37. 37.
    Kubota R, Kubota K, Yamada S (1992) Enhancement of the effects of anticancer agents on B16 melanoma cells by combination with cepharanthine. II. Antimetabolite, alkylating agent nitrosourea. Jpn J Cancer Chemother 19:2169–2174Google Scholar
  38. 38.
    Miyauchi T, Ono M, Yatabe M, Akasu M, Orita K (1988) Combined antitumor effect of cepharanthin and 5-fluorouracil on human tumor cell proliferation. Igaku To Yakugaku 20: 1261–1266Google Scholar
  39. 39.
    Gresser I, Maur C, Tovey M (1978) Efficacy of combined interferon-cyclophosphamide therapy after diagnosis of lymphoma in AKR mice. Eur J Cancer 14:97–99Google Scholar
  40. 40.
    Chirigos MA, Pearson JW (1973) Cure of murine leukemia with drug and interferon treatment. J Natl Cancer Inst 51:1367–1368Google Scholar
  41. 41.
    Slater LM, Wetzel MW, Cesaria T (1981) Combined interferonantimetabolite therapy of murine L1210 leukemia. Cancer 48:5–9Google Scholar
  42. 42.
    Creasey AA, Bartholomew JC, Merigan TC (1980) Role of G0-G1 arrest in the inhibition of tumor cell growth by interferon. Proc Natl Acad Sci USA 77:1471–1475Google Scholar
  43. 43.
    Ono M (1987) Direct effects of cepharanthin on the human tumor cell lines: analysis of tumor growth inhibition and cell cycle traverse in vitro. Ther Res 7:1349–1354Google Scholar
  44. 44.
    Gresser I, Maury C, Brouty-Boy D (1972) On the mechanism of the antitumor effect of interferon in mice. Nature 239:167–168Google Scholar
  45. 45.
    Chatterjee S, Cheung HC, Hunter E (1982) Interferon inhibits Sendai virus-induced cell fusion: an effect on cell membrane fluidity. Proc Natl Acad Sci USA 79:835–839Google Scholar
  46. 46.
    Wang E, Pfeffer LM, Tamm I (1981) Interferon increases the abundance of submembranous microfilaments in HeLa-S3 cells in suspension culture. Proc Natl Acad Sci USA 78:6281–6285Google Scholar
  47. 47.
    Brouty-By D, Zetter BR (1980) Inhibition of cell motility by interferon. Science 208:516–518Google Scholar
  48. 48.
    Attalah AM, Needy CF, Noguchi CD, Elisberg BL (1979) Enhancement of carcinoembryonic antigen expression by interferon. Int J Cancer 24:49–52Google Scholar
  49. 49.
    Huet D, Gresser I, Bandu MT, Lindahl P (1974) Increased binding of concanavalin A to interferon-treated murine leukemia L1210 cells. Proc Soc Exp Biol Med 147:52–57Google Scholar
  50. 50.
    Imai K, Ah-Kau NG, Glassy MC, Ferrone S (1981) Differential effect of interferon on the expression of tumor-associated antigens and histocompatibility agents on human melanoma cells. J Immunol 127:505–509Google Scholar
  51. 51.
    Liao S-K, Kwong PC, Khosravi M, Dent PB (1982) Enhanced expression of melanoma-associated antigens and β2-microglobulin on cultured human melanoma cells by interferon. J Natl Cancer Inst 68:19–25Google Scholar
  52. 52.
    Wivel NA, Pitha PM (1982) Interferon treatment of murine Meth-A sarcoma cells: effects on the malignant phenotype and expression on tumor-specific and H-2 antigens. Int J Cancer 30:649–654Google Scholar
  53. 53.
    Akiyama S, Gottesman MM, Hanover JA Fitzgerald DJP, Willingham MC, Pastan I (1984) Verapamil enhances the toxicity of conjugates of epidermal growth factor withPseudomonas exotoxin and antitransferrin receptor withPseudomonas exotoxin. J Cell Physiol 120:271–279Google Scholar
  54. 54.
    Kuratomi Y, Akiyama S, Ono M, Shiraishi N, Shimada T, Ohkuma S, Kuwano M (1985) Thioridazine enhances lysosomal accumulation of epidermal growth factor and toxicity of conjugates of epidermal growth factor withPseudomonas exotoxin. Exp Cell Res 162:436–448Google Scholar
  55. 55.
    Akiyama S, Shiraishi N, Yoshimura A, Nakagawa M Yamaguchi T, Shimada T, Kuwano M (1987) Enhancement by a synthetic isoprenoid of the toxicity of conjugates of epidermal growth factor withPseudomonas exotoxin. Biochem Pharmacol 36:861–868Google Scholar
  56. 56.
    Akiyama S, Tomita K, Kuwano M (1985) The effect of calcium antagonists on the proteolytic degradation of low-density lipoprotein in HeLa cells. Exp Cell Res 158:192–204Google Scholar
  57. 57.
    Sato T, Kanaho Y, Fujii T (1980) Relation of the characteristic action of biscoclaurine alkaloids on the erythrocyte membrane and their incorporation into the membrane. Cell Struct Funct 5:155–163Google Scholar
  58. 58.
    Ono M, Fujiwara R, Tagashira Y, Matsui T, Oohashi K, Kamikawa Y, Tanaka N, Konaga E, Orita K (1981) Effect of cepharanthine on the ADCC activity of spleen cells obtained from the tumor-bearing mice. Jpn J Cancer Chemother 8:1565–1569Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Minoru Ono
    • 1
  • Noriaki Tanaka
    • 1
  • Kunzo Orita
    • 1
  1. 1.First Department of SurgeryOkayama University Medical SchoolOkayamaJapan

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