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

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‐γ and abolished in mice by treatment with asialoGM‐1 but not CD8β 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‐γ 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. ( Cancer Sci 2009)