Isolation of an anti-angiogenic substance from Agaricus blazei Murill: its antitumor and antimetastatic actions.
We previously found that ergosterol isolated from Agaricus blazei inhibited tumor growth through the inhibition of tumor-induced neovascularization. In the present study, we isolated further anti-angiogenic substances (A-1 and A-2) from this fungus using an assay system of angiogenesis induced by Matrigel supplemented with vascular endothelial growth factor, and A-1 was identified as sodium pyroglutamate. Next, we examined the antitumor and antimetastatic actions of A-1 using Lewis lung carcinoma (LLC)-bearing mice. A-1 (30, 100 and 300 mg/kg) inhibited tumor growth and metastasis to the lung. The reduction of the numbers of splenic lymphocytes, CD4+ and CD8+ T cells in LLC-bearing mice was inhibited by the oral administration of A-1 (30, 100 and 300 mg/kg). Further, A-1 increased the number of apoptotic cells of tumors and the numbers of CD8+ T and natural killer cells invading the tumors, and inhibited the increase of von Willebrand factor expression (a measure of angiogenesis) in the tumors. These results suggest that the antitumor and antimetastatic actions of A-1 (sodium pyroglutamate) may be associated with inhibition of the reduction of immune response caused by the tumor growth and tumor-induced neovascularization. This is the first report showing that sodium pyroglutamate isolated from A. blazei as an anti-angiogenic substance has potent antitumor and antimetastatic actions, as well as immune-modulatory activity, in tumor-bearing mice.
Kimura
Yoshiyuki
Y
Second Department of Medical Biochemistry, School of Medicine, Shigenobu Station, Ehime University, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan. yokim@m.ehime-u.ac.jp
Kido
Tadashi
T
Takaku
Takeshi
T
Sumiyoshi
Maho
M
Baba
Kimiye
K
D000284:Administration, Oral; D000364:Agaricus / Q000737:chemistry*; D020533:Angiogenesis Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000473:pathology / Q000517:prevention & control*; D003094:Collagen; D004338:Drug Combinations; D005260:Female; D007694:Killer Cells, Natural / Q000473:pathology; D007797:Laminin; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011509:Proteoglycans; D011761:Pyrrolidonecarboxylic Acid / Q000302:isolation & purification / Q000494:pharmacology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D011761:Pyrrolidonecarboxylic Acid