Abstract
Purpose: The Basidiomycete fungus Agaricus blazei Murill has traditionally been used as a health food for the prevention of cancer. Methods: We examined whether beta-(1–6)-D-glucan extracted from A. blazei is a potential anticancer agent in an in vitro and in vivo animal model. Results: Here we show that (1) beta-glucan had cytotoxic effect against human ovarian cancer HRA cells, but not against murine Lewis lung cancer 3LL cells, in vitro; (2) beta-glucan promotes p38 MAPK activity for suppressing HRA cell proliferation and amplifying the apoptosis cascade; (3) beta-glucan stimulates translocation of the proapoptotic protein, Bax, from the cytosol to mitochondria, cytochrome c release, and subsequent caspase-9 activation; (4) treatment with SB203580, a p38 MAPK-specific inhibitor, suppresses beta-glucan-induced effects, indicating that activation of p38 MAPK is involved in the suppression of cell proliferation and mitochondrial activation-mediated cell death pathway; (5) in mice, oral supplementation with beta-glucan reduces pulmonary metastasis of 3LL cells and peritoneal disseminated metastasis of HRA cells and inhibits the growth of these metastatic tumors in lung or peritoneal cavity, in part, by suppressing uPA expression; and (6) in an in vivo experimental metastasis assay, however, the oral supplementation with beta-glucan after i.v. tumor cell inoculation did not reduce the number of lung tumor colonies. Conclusion: Treatment with beta-glucan may be beneficial for cancer patients with or at risk for metastasis. The beta-glucan-dependent signaling pathways are critical for our understanding of anticancer events and development of cancer therapeutic agents.
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Abbreviations
- 3LL:
-
Murine Lewis lung carcinoma
- MAPK:
-
Mitogen-activated protein kinase
- uPA:
-
Urokinase-type plasminogen activator
- FCS:
-
Fetal calf serum
- ERK:
-
Extracellular signal-regulated kinase
- JNK:
-
c-Jun N-terminal kinase
- TGF-β:
-
Transforming growth factor-beta
References
Aguirre-Ghiso JA, Estrada Y, Liu D, Ossowski L (2003) ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 63:1684–1695
Beier RC (1990) Natural pesticides and bioactive components in foods. Rev Environ Contam Toxicol 113:47–137
Bein K, Odell-Fiddler ET, Drinane M (2004) Role of TGF-beta1 and JNK signaling in capillary tube patterning. Am J Physiol Cell Physiol 287:C1012–C1022
Chen J, Baskerville C, Han Q, Pan ZK, Huang S (2001) Alpha(v) integrin, p38 mitogen-activated protein kinase, and urokinase plasminogen activator are functionally linked in invasive breast cancer cells. J Biol Chem 276:47901–47905
Frey RS, Singletary KW (2003) Genistein activates p38 mitogen-activated protein kinase, inactivates ERK1/ERK2 and decreases Cdc25C expression in immortalized human mammary epithelial cells. J Nutr 133:226–231
Fujimiya Y, Suzuki T, Oshiman K, Kobori H, Moriguchi K, Nakashima H, Matumoto Y, Takahara S, Ebina T, Katakura R (1998) Selective tumoricidal effect of soluble proteoglucan extracted from the Basidiomycete, Agaricus blazei Murill, mediated via natural killer cell activation and apotosis. Cancer Immunol Immunother 46:147–159
Han Q, Leng J, Bian D, Mahanivong C, Carpenter KA, Pan ZK, Han J, Huang S (2002) Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells. J Biol Chem 277:48379–48385
Itoh H, Ito H, Amano H, Noda H (1994) Inhibitory action of (1–6)-ß-glucan-protein complex (FIII 020b) isolated from Agaricus blazei Murill (“Himematsutake”) on Meth A fibrosarcoma-bearing mice and its antitumor mechanism. Jpn J Pharmacol 66:265–271
Jiang J, Slivova V, Valachovicova T, Harvey K, Sliva D (2004) Ganoderma lucidum inhibits proliferation and induces apoptosis in human prostate cancer cells PC-3. Int J Oncol 24:1093–1099
Kawagishi H, Kanao T, Inagaki R, Mituno T, Shimura K, Itoh H, Hagiwara T, Nakamura T (1990) Formolysis of a potent antitumor (1–6)-ß-glucan-protein complex from Agaricus blazei fruiting bodies and antitumor activity of the resulting products. Carbohydr Polym 12:393–403
Kim MR, Lee JY, Park MT, Chun YJ, Jang YJ, Kang CM, Kim HS, Cho CK, Lee YS, Jeong HY, Lee SJ (2001) Ionizing radiation can overcome resistance to TRAIL in TRAIL-resistant cancer cells. FEBS Lett 505(1):179–184
Kobayashi H, Gotoh J, Shinohara H, Moniwa N, Terao T (1994) Inhibition of the metastasis of Lewis lung carcinoma by antibody against urokinase-type plasminogen activator in the experimental and spontaneous metastasis model. Thromb Haemost 71:474–480
Kobayashi H, Shinohara H, Fujie M, Gotoh J, Itoh M, Takeuchi K, Terao T (1995) Inhibition of metastasis of Lewis lung carcinoma by urinary trypsin inhibitor in experimental and spontaneous metastasis models. Int J Cancer 63:4554–4562
Kobayashi H, Yagyu T, Inagaki K, Kondo T, Suzuki M, Kanayama N, Terao T (2004) Bikunin plus paclitaxel markedly reduces tumor burden and ascites in mouse model of ovarian cancer. Int J Cancer 110:134–139
Kodama N, Komuta K, Nanba H (2002) Can maitake MD-fraction aid cancer patients? Altern Med Rev 7:236–239
Lee YL, Kim HJ, Lee MS, Kim JM, Han JS, Hong EK, Kwon MS, Lee MJ (2003) Oral administration of Agaricus blazei (H1 strain) inhibited tumor growth in a sarcoma 180 inoculation model. Exp Anim 52:371–375
Liu Q, Chen T, Chen H, Zhang M, Li N, Lu Z, Ma P, Cao X (2004) Triptolide (PG-490) induces apoptosis of dendritic cells through sequential p38 MAP kinase phosphorylation and caspase 3 activation. Biochem Biophys Res Commun 319:980–986
Mizuno T, Inagaki R, Kanno T, Hagiwara T, Nakamura T, Itoh T, Shimura K, Sumiya T, Asakura A (1990) Antitumor activity and some properties of water-soluble polysaccharides from “Himematsutake”, the fruiting body of Agaricus blazei Murill. Agric Biol Chem 54:2889–2896
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63
Nakazato H, Koike A, Saji S, Ogawa N, Sakamoto J (1994) Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Study group of immunochemotherapy with PSK for gastric cancer. Lancet 343(8906):1122–1126
Ohno N, Furukawa M, Miura NN, Adachi Y, Motoi M, Yadomae T (2001) Antitumor beta glucan from the cultured fruit body of Agaricus blazei. Biol Pharm Bull 24:820–828
Oshiman K, Fujimiya Y, Ebina T, Suzuki I, Noji M (2002) Orally administered beta-1,6-D-polyglucose extracted from Agaricus blazei results in tumor regression in tumor-bearing mice. Planta Med 68:610–614
Ossowski L, Reich E (1983) Antibodies to plasminogen activator inhibit human tumor metastasis. Cell 35:611–619
Ostrowski LE, Ahsan A, Suthar BP, Pagast P, Bain DL, Wong C, Patel A, Schultz RM (1986) Selective inhibition of proteolytic enzymes in an in vivo mouse model for experimental metastasis. Cancer Res 46:4121–4128
Otsuka F, Yao Z, Lee TH, Yamamoto S, Erickson GF, Shimasaki S (2000) Bone morphogenetic protein-15. Identification of target cells and biological functions. J Biol Chem 275:39523–39528
Park MT, Choi JA, Kim MJ, Um HD, Bae S, Kang CM, Cho CK, Kang S, Chung HY, Lee YS, Lee SJ (2003) Suppression of extracellular signal-related kinase and activation of p38 MAPK are two critical events leading to caspase-8- and mitochondria-mediated cell death in phytosphingosine-treated human cancer cells. J Biol Chem 278:50624–50634
Pei XH, Nakanishi Y, Takayama K, Bai F, Kawasaki M, Hara N (1998) G-CSF increases secretion of urokinase-type plasminogen activator by human lung cancer cells. Clin Exp Metastasis 16:551–558
Shin BA, Yoo HG, Kim HS, Kim MH, Hwang YS, Chay KO, Lee KY, Ahn BW, Jung YD (2003) P38 MAPK pathway is involved in the urokinase plasminogen activator expression in human gastric SNU-638 cells. Oncol Rep 10:1467–1471
Sliva D, Labarrere C, Slivova V, Sedlak M, Lloyd FP Jr, Ho NW (2002) Ganoderma lucidum suppresses motility of highly invasive breast and prostate cancer cells. Biochem Biophys Res Commun 298:603–612
Suzuki M, Kobayashi H, Tanaka Y, Hirashima Y, Kanayama N, Takei Y, Saga Y, Suzuki M, Itoh H, Terao T (2003) Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cell line by overexpression of bikunin. Int J Cancer 104:289–302
Sveinbjornsson B, Rushfeldt C (1998) Inhibition of establishment and growth of mouse liver metastasis after treatment with interferon gamma and beta-1,3-D-glucan. Hepatol 27:1241–1248
Takaku T, Kimura Y, Okuda H (2001) Isolation of an antitumor compound from Agaricus blazei Murill and its mechanism of action. J Nutr 131:1409–1413
Torisu M, Hayashi Y, Ishimitsu T, Fujimura T, Iwasaki K, Katano M, Yamamoto H, Kimura Y, Takesue M, Kondo M (1990) Significant prolongation of disease-free period gained by oral polysaccharide K (PSK) administration after curative surgical operation of colorectal cancer. Cancer Immunol Immunother 31:261–268
Acknowledgements
Agaricus blazei was obtained from K. Naito (DreamWorld Co., Ltd.). This work was supported by a grant-in-aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (to H.K.), by grants from the Fuji Foundation for Protein Research (H.K.), the Kanzawa Medical Foundation (H.K.), Sagawa Cancer Research foundation (H.K.), and Aichi Cancer Research foundation (H.K).
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Kobayashi, H., Yoshida, R., Kanada, Y. et al. Suppressing effects of daily oral supplementation of beta-glucan extracted from Agaricus blazei Murill on spontaneous and peritoneal disseminated metastasis in mouse model. J Cancer Res Clin Oncol 131, 527–538 (2005). https://doi.org/10.1007/s00432-005-0672-1
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DOI: https://doi.org/10.1007/s00432-005-0672-1