Enhancement of antitumor natural killer cell activation by orally administered Spirulina extract in mice

Cancer Sci. 2009 Aug;100(8):1494-501. doi: 10.1111/j.1349-7006.2009.01188.x. Epub 2009 May 6.


Oral administration of hot-water extract of Spirulina, cyanobacterium Spirulina platensis, leads to augmentation of NK cytotoxicity in humans. Here, we applied to syngeneic tumor-implant mice (C57BL/6 versus B16 melanoma) Spirulina to elucidate the mechanism of raising antitumor NK activation. A B16D8 subcell line barely expressed MHC class I but about 50% expressed Rae-1, a ligand for NK activation receptor NKG2D. The Rae-1-positive population of implant B16 melanoma was effectively eliminated in the tumor mass progressed in mice. This antitumor activity was induced in parallel with IFN-gamma and abolished in mice by treatment with asialoGM-1 but not CD8beta Ab, suggesting the effector is NK cell. NK cell activation occurred in the spleen of wild-type mice medicated with Spirulina. This Spirulina-mediated enhanced NK activation was abrogated in MyD88 -/- mice but not in TICAM-1 -/- mice. The NK activating properties of Spirulina depending on MyD88 were confirmed with in vitro bone marrow-derived dendritic cells expressing TLR2/4. In D16D8 tumor challenge studies, the antitumor effect of Spirulina was abolished in MyD88 -/- mice. Hence, orally administered Spirulina enhances tumoricidal NK activation through the MyD88 pathway. Spirulina exerted a synergistic antitumor activity with BCG-cell wall skeleton, which is known to activate the MyD88 pathway via TLR2/4 with no NK enhancing activity. Spirulina and BCG-cell wall skeleton synergistically augmented IFN-gamma production and antitumor potential in the B16D8 versus C57BL/6 system. We infer from these results that NK activation by Spirulina has some advantage in combinational use with BCG-cell wall skeleton for developing adjuvant-based antitumor immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / metabolism
  • Administration, Oral
  • Animals
  • BCG Vaccine / immunology
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / immunology
  • Cell Wall / immunology
  • Dendritic Cells / immunology
  • Drug Synergism
  • Female
  • Interferon-gamma / biosynthesis
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation*
  • Melanoma, Experimental / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / immunology
  • NK Cell Lectin-Like Receptor Subfamily K / immunology
  • Powders
  • Specific Pathogen-Free Organisms
  • Spirulina / immunology*
  • Spleen / cytology
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / metabolism


  • Adjuvants, Immunologic
  • BCG Vaccine
  • Myeloid Differentiation Factor 88
  • NK Cell Lectin-Like Receptor Subfamily K
  • Powders
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Interferon-gamma