Medication Guide App

Lentinan

Scientific Name(s): Lentinula edodes (Berk.) Pegler. Family: Tricholomataceae

Common Name(s): Shiitake , snake butter , pasania fungus , forest mushroom , hua gu . (Also found in Selected Vegetables and Sun's Soup , which are promoted for cancer and HIV therapy.)

Uses

Lentinan is used widely in Japan and China as an adjuvant to cancer chemotherapy. It is also used for upregulating the immune system; however, the number of quality clinical trials and studies published in English language, peer-reviewed journals is limited.

Dosing

The isolated polysaccharide lentinan from shiitake culture has been used intravenously (IV) at doses of 2 to 10 mg on a weekly schedule as adjunctive therapy for HIV as well as for cancer, primarily in Japan. Oral shiitake extract was used in a trial for the treatment of prostate cancer at 8 g/day for 6 months.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None reported.

Adverse Reactions

Clinical trials report few adverse events at normal dosages. Case reports exist of allergic/contact dermatitis, asthma, rhinitis, and hypersensitivity pneumonitis in shiitake workers. Shiitake dermatitis has been described as a reaction to the ingestion of raw or partially cooked mushrooms and may be a toxic reaction to lentinan. Photosensitivity reactions have also been reported. Anaphylaxis, granulocytopenia, and elevated liver enzymes were reported after rapid (10 minutes) IV infusion in an HIV trial.

Toxicology

The shiitake mushroom is edible and has generally not been associated with toxicity. In a study in mice, high-dose shiitake resulted in increases in plasma bilirubin and plasma creatine kinase.

Botany

Lentinan is a polysaccharide derived from the vegetative parts of the edible Japanese shiitake mushroom. It is the cell wall constituent extracted from the fruiting bodies or mycelium of L. edodes . The light, amber fungi are found on fallen broad-leaf trees, such as chestnut, beech, or mulberry. They have decurrent, even, or ragged gills, a stem, and are covered with delicate white flocking. Shiitake mushrooms are commonly sold in food markets in Asia and are now widely available in the United States, Canada, and Europe. 1 Synonyms include Cortinellus edodes , Armillaria edodes , Cortinellus shiitake , and Tricholomopsis edodes .

History

Shiitake has been recognized in Japan and China as a food and medicine for thousands of years. Lentinan was isolated from edible shiitake mushrooms used in traditional Asian cooking and herbal medicine. Extracts of these mushrooms are now being incorporated into over-the-counter dietary supplements designed to improve the immune system. 1

Chemistry

The shiitake mushroom contains starch, fiber, chitin, and high amounts of protein. 2 Lentinan is a water-soluble, high molecular weight polysaccharide in a triple helix structure, containing only glucose molecules with mostly (1-3)-beta-D-glucan linkages in the regularly branched main chain with 2 beta (1,6)-D-glucopyranoside branchings for every 5 beta-(1,3)-glucopyranoside linear linkages. 1 , 3 Lentinan, which is thermolabile, 4 is found in very low concentrations in fresh shiitake mushrooms (approximately 0.02%); at least 5 additional polysaccharides have been isolated from L. edodes . 5

Other constituents of interest found in the mushroom include the antioxidant phenolic compounds gallic acid, protocatechuic acid, and catechin 6 ; as well as eritadenine, 7 , 8 selenium (as selenomethionine), 9 ergosterol, vitamin D, and calcium. 10 , 11

Uses and Pharmacology

Cancer

Lentinan has demonstrated inhibition of tumor growth and stimulation of apoptosis in animal experiments and in vitro studies. Increased survival times and improved quality of life have also been reported. However, the number of quality clinical trials and studies published in English language, peer-reviewed journals is limited. 12 , 13 , 14 Lentinan is approved in Japan as a pharmaceutical product and is commonly used as an adjuvant for the treatment of certain cancers in Japan and China. 12

Animal data

Animal and in vitro studies show significant antitumor and antimetastatic activity of lentinan, 5 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 increased longevity, 3 and synergism with other chemotherapeutic agents. 23 , 24 , 25

Clinical data

Case reports and open-label, nonrandomized studies form the bulk of evidence for lentinan in cancer therapy, with many of these studies being conducted in Japanese populations and commonly in combination with other therapies. 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 Data are sufficient to recommend clinical applications for lentinan but are sufficient to warrant further large scale, quality trials. 12 , 13 Clinical trials with negative results (ie, no effect in prostate cancer) have been published. 13 , 40 Resistance to lentinan chemo-immunotherapy has also been reported. 41

Immune system effects

Lentinan and other beta-glucans have demonstrated immunomodulatory properties in animal experiments and in vitro studies. Multiple pathways have been described for the effects observed in the immune system, including upregulation of T-cell, cytokine, monocyte, tumor necrosis factor, natural killer cell, complement activation and other macrophage responses. 22 , 27 , 30 , 32 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51

Animal data

In mice pretreated with lentinan, significant reductions in parasitemia and increased survival were demonstrated against malaria. 52 Similar results were found in rabbits with induced septic insult and other microbial infections. 53 An increased antibody titer was demonstrated in vaccinated chickens treated with sulfated lentinan for 3 days. 54 Other studies report on enhanced antitumor activity by lentinan-induced multiple immune mechanisms 3 but note that in vivo effects are more difficult to demonstrate than in vitro. 43

Clinical data

Clinical trials are lacking.

Other effects
Antimicrobial effects

A wide in vitro spectrum of activity against human pathogens has been described, including activity against staphylococcus aureus , methicillin-resistant staphylococcus aureus , 43300 and ciprofloxacin-resistant Pseudomonas strains. 55 Antiviral activity has also been evaluated in vitro against HIV and vesicular stomatitis virus. 56 , 57 , 58 , 59

Cholesterol-lowering

Animal experiments have shown varying results. 8 , 60 , 61 An effect on the lipid profile has been attributed to the ergosterol and eritadenine constituents found in the mushroom. Clinical studies are lacking.

Osteoporosis

The vitamin D and calcium content of shiitake mushrooms can be enhanced during cultivation by the addition of egg shells to the growing media and growth under ultraviolet light. 10 , 11 Animal experiments have shown increased femur and tibia mineralization, increased serum calcium and increased duodenal and renal calcium transport genes with enhanced shiitake diets. 10 , 11

Dosage

Lentinan is a high molecular weight polysaccharide, and is usually administered by the intraperitoneal route because of poor oral bioavailability and rapid metabolism. 12 , 14

The isolated polysaccharide lentinan from shiitake culture has been used IV at doses of 2 to 10 mg on a weekly schedule as adjunctive therapy for HIV as well as for cancer, primarily in Japan. 58

Oral shiitake extract was used in a trial for the treatment of prostate cancer at 8 g/day for 6 months without significant effect on the disease progression. 40

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. 13

Interactions

None reported. 12

Adverse Reactions

Clinical trials report few adverse events at normal dosages. 12 , 15 , 62 Severe events were reported (anaphylaxis, granulocytopenia, elevated liver enzymes) after rapid IV infusion in HIV patients. 58

Case reports exist of allergic/contact dermatitis, asthma, and rhinitis in shiitake workers, 8 , 63 as well as hypersensitivity pneumonitis. 64 Shiitake dermatitis has been described as a reaction to the ingestion of raw or partially cooked mushrooms and may be a toxic reaction to lentinan. 4 , 65 Positive skin prick tests have been described in patients with shiitake-related protein contact dermatitis. 63 Photosensitivity reactions 13 , 14 and GI upset have also been reported. 66

Toxicology

The shiitake mushroom is edible and has generally not been associated with toxicity. In a study in mice, high-dose shiitake resulted in increases in plasma bilirubin and plasma creatine kinase. 8

In animals, lentinan shows little toxicity. In mice, the lethal dose (LD 50 ) is greater than 1,500 mg/kg (intraperitoneally). 5

Bibliography

1. Hobbs C. Medicinal Mushrooms . Santa Cruz, CA: Botanica Press; 1995;125.
2. Dikeman CL, Bauer LL, Flickinger EA, Fahey GC Jr. Effects of stage of maturity and cooking on the chemical composition of select mushroom varieties. J Agric Food Chem . 2005;53(4):1130-1138.
3. Zheng R, Jie S, Hanchuan D, Moucheng W. Characterization and immunomodulating activities of polysaccharide from Lentinus edodes . Int Immunopharmacol . 2005;5(5):811-820.
4. Garg S, Cockayne SE. Shiitake dermatitis diagnosed after 16 years! Arch Dermatol . 2008;144(9):1241-1242.
5. Chihara G, hamuro J, Maeda Y, Arai Y, Fukuoka F. Fractionation and purification of the polysaccharides with marked anititumor activity, especially lentinan, from Lentinus edodes (Berk.) Sing (an edible mushroom). Cancer Res . 1970;30(11):2776.
6. Kim MY, Seguin P, Ahn JK, et al. Phenolic compound concentration and antioxidant activities of edible and medicinal mushrooms from Korea. J Agric Food Chem . 2008;56(16):7265-7270.
7. Enman J, Rova U, Berglund KA. Quantification of the bioactive compound eritadenine in selected strains of shiitake mushroom ( Lentinus edodes ). J Agric Food Chem . 2007;55(4):1177-1180.
8. Nieminen P, Kärjä V, Mustonen AM. Myo- and hepatotoxic effects of cultivated mushrooms in mice. Food Chem Toxicol . 2009;47(1):70-74.
9. Ogra Y, Ishiwata K, Ruiz Encinar J, Lobiński R, Suzuki KT. Speciation of selenium in selenium-enriched shiitake mushroom, Lentinula edodes . Anal Bioanal Chem . 2004;379(5-6):861-866.
10. Jasinghe VJ, Perera CO, Barlow PJ. Bioavailability of vitamin D2 from irradiated mushrooms: an in vivo study. Br J Nutr . 2005;93(6):951-955.
11. Lee GS, Byun HS, Yoon KH, Lee JS, Choi KC, Jeung EB. Dietary calcium and vitamin D2 supplementation with enhanced Lentinula edodes improves osteoporosis-like symptoms and induces duodenal and renal active calcium transport gene expression in mice. Eur J Nutr . 2009;48(2):75-83.
12. Sullivan R, Smith JE, Rowan NJ. Medicinal mushrooms and cancer therapy: translating a traditional practice into Western medicine. Perspect Biol Med . 2006;49(2):159-170.
13. Boon H, Wong J. Botanical medicine and cancer: a review of the safety and efficacy. Expert Opin Pharmacother . 2004;5(12):2485-2501.
14. Yeung KS, Gubili J. Shiitake Mushroom ( Lentinula edodes ). J Soc Integr Oncol . 2008;6(3):134-135.
15. Jeannin JF, Lagadec P, Pelletier H, et al. Regression induced by lentinan, or peritoneal carcinomatoses in a model of colon cancer in rat. Int J Immunopharm . 1988;10(7):855-861.
16. Lapis K, Timár J, Pápáy J, Paku S, Szende B, Ladányi A. Experiemental metastasis inhibition by pretreatment of the host. Arch Geschwulstforschung . 1990;60(2):97-102.
17. Shen J, Tanida M, Fujisaki Y, Horii Y, Hashimoto K, Nagai K. Effect of the culture extract of Lentinus edodes mycelia on splenic sympathetic activity and cancer cell proliferation. Auton Neurosci . 2009;145(1-2):50-54.
18. Gu YH, Belury MA. Selective induction of apoptosis in murine skin carcinoma cells (CH72) by an ethanol extract of Lentinula edodes . Cancer Lett . 2005;220(1):21-28.
19. Zhang L, Li X, Xu X, Zeng F. Correlation between antitumor activity, molecular weight, and conformation of lentinan. Carbohydr Res . 2005;340(8):1515-1521.
20. Fang N, Li Q, Yu S, Zhang J, He L, Ronis MJ, Badger TM. Inhibition of growth and induction of apoptosis in human cancer cell lines by an ethyl acetate fraction from shiitake mushrooms. J Altern Complement Med . 2006;12(2):125-132.
21. Miyaji CK, Poersch A, Ribeiro LR, Eira AF, Cólus IM. Shiitake ( Lentinula edodes (Berkeley) Pegler) extracts as a modulator of micronuclei induced in HEp-2 cells. Toxicol In Vitro . 2006;20(8):1555-1559.
22. Israilides C, Kletsas D, Arapoglou D, et al. In vitro cytostatic and immunomodulatory properties of the medicinal mushroom Lentinula edodes . Phytomedicine . 2008;15(6-7):512-519.
23. Hamuro J, Takatsuki F, Suga T, Kikuchi T, Suzuki M. Synergistic antimetastatic effects of lentinan and interleukin 2 with pre-and post-operative treatments. Jpn J Cancer Res . 1994;85(12):1288-1297.
24. Yamasaki K, Sone S, Yamashita T, Ogura T. Synergistic induction of lymphokine (IL-2)-activated killer activity by IL-2 and the polysaccharide lentinan, and therapy of spontaneous pulmonary metastases. Cancer Immunol Immunother . 1989;29(2):87-92.
25. Yang P, Liang M, Zhang Y, Shen B. Clinical application of a combination therapy of lentinan, multi-electrode RFA and TACE in HCC. Adv Ther . 2008;25(8):787-794.
26. Maekawa S, Saku M, Kinugasa T, et al. A case report of advanced gastric cancer remarkably responding to mitomycin C, aclacinomycin A, SF-SP and lentinan combination therapy [in Japanese]. Gan to Kagaku Ryoho . 1990;17:137-140.
27. Tanabe H, Imai N, Takechi K. Studies on usefulness of postoperative adjuvant chemotherapy with lentinan in patients with gastrointestinal cancer [in Japanese]. Nippon Gan Chiryo Gakki Shi . 1990;25(8):1657-1667.
28. Taguchi T. Clinical efficacy of lentinan on patients with stomach cancer: end point results of a four-year follow-up survey. Cancer Detect Prev Suppl . 1987;1:333-349.
29. Mio H, Terabe K. Postoperative immunochemotherapy for gastric carcinoma with peritoneal disemination – the effects with the combination of CDDP, 5-FU and lentinan [in Japanese]. Gan To Kagaku Ryoho . 1994;21(13):531-534.
30. Suzuki M, Higuchi S, Taki Y, Taki S, Miwa K, Hamuro J. Induction of endogenous lymphokine-activated killer activity by combined administration of lentinan and interleukin 2. Int J Immunopharmacol . 1990;12(6):613-623.
31. Ogawa K, Watanabe T, Katsube T, et al. Study on intratumor admionistration of lentinan – primary changes in cancerous tissues [in Japanese]. Gan To Kagaku Ryoho . 1994;21(13):2101-2104.
32. Hazama S, Oka M, Yoshino S, et al. Clinical effects and immunological analysis of intraabdominal and intrapleural injection of lentinan for malignant ascites and pleural effusion of gastric carcinoma [in Japanese]. Gan To Kagaku Ryoho . 1995;22(11):1595-1597.
33. Tari K, Satake I, Nakagomi K, et al. Effect of lentinan for advanced prostate carcinoma [in Japanese]. Hinyokika Kiyo . 1994;40(2):119-123.
34. Kosaka A, Kuzuoka M, Yamafuji K, et al. Synergistic action of lentinan (LNT) with endocrine therapy of breast cancer in rats and humans [in Japanese]. Gan To Kagaku Ryoho . 1987;14(2):516-522.
35. Shimizu H, Inoue M, Shimizu C, et al. Augmentation of antitumor effect of recombinant interleukin-2 activated killer cells by the administration of rIL-2 and lentinan. Nippon Sanka Fujinka Gakkai Zasshi . 1988;40(12):1899-1900.
36. Shimizu Y, Chen JT, Hirai T, et al. Augmentative effect of lentinan on immune responses of pelvic lymph node lymphocytes in patients with uterine cervical cancer. Nippon Sanka Fujinka Gakkai Zasshi . 1988;40:1557-1558.
37. Shimizu Y, Chen JT, Shiokawa S, et al. Antigenic phenotype of the lymphocytic component of regional lymph nodes in patients with cervical cancer and its modulation by lentinan [in Japanese]. Nippon Sanka Fujinka Gakkai Zasshi . 1990;42:37-44.
38. Oka M, Yoshino S, Hazama S, Shimoda K, Suzuki T. Antigenic phenotype of the lymphocytic component of regional lymph nodes in patients with cervical cancer and its modulation by lentinan. Biotherapy . 1992;5(5):107-112.
39. Fujimoto K, Tomonaga M, Goto S. A case of recurrent ovarian cancer successfully treated with adoptive immunotherapy and lentinan. Anticancer Res . 2006;26(6A):4015-4018.
40. deVere White RW, Hackman RM, Soares SE, et al. Effects of a mushroom mycelium extract on the treatment of prostate cancer. Urology . 2002;60(4):640-644.
41. Hamuro J, Kikuchi T, Takatsuki F, Suzuki M. Cancer cell progression and chemoimmunotherapy—dual effects in the induction of resistance to therapy. Br J Cancer . 1996;73(4):465-471.
42. Yin Y, Fu W, Fu M, He G, Traore L. The immune effects of edible fungus polysaccharides compounds in mice. Asia Pac J Clin Nutr . 2007;16(suppl 1):258-260.
43. Yu S, Weaver V, Martin K, Cantorna MT. The effects of whole mushrooms during inflammation. BMC Immunol . 2009;10:12.
44. Lee JY, Kim JY, Lee YG, Rhee MH, Hong EK, Cho JY. Molecular mechanism of macrophage activation by Exopolysaccharides from liquid culture of Lentinus edodes . J Microbiol Biotechnol . 2008;18(2):355-364.
45. Péter G, Károly V, Imre B, János F, Kaneko Y. Effects of lentian on cytotoxic functions of human lymphocytes. Immunopharmacol Immunotoxical . 1988;10(2):157-163.
46. Takeshita K, Saito N, Sato Y, et al. Diversity of complement activation of lentinan, an antitumor polysaccharide, in gastric cancer patients [in Japanese]. Nippon Geka Gakkai Zasshi . 1991;92(1):5-11.
47. Tani M, Tanimura H, Yamaue H, et al. Augmentation of lymphokine-activated killer cell activity by lentinan. Anticancer Res . 1993;13(5C):1773-1776.
48. Tani M, Tanimura H Yamaue H, et al. In vitro generation of activated natural killer cell sand cytotoxic macrophages with lentinan. Eur J Clin Pharmacol . 1992;42(6):623-627.
49. Arinaga S, Karimine N, Takamuku K, et al. Enhanced induction of lymphokine-activated killer activity after lentinan administration in patients with gastric carcinoma. Int J Immunopharm . 1992;14(4):535-539.
50. Arinaga S, Karimine N, Nanbara S, et al. Enhanced production of interleukin 1 and tumor necrosis factor by peripheral monocytes after lentinan administration in patients with gastric carcinoma. Int J Immunopharm . 1992;14(1):43-47.
51. Akamatsu S, Watanabe A, Tamesada M, et al. Hepatoprotective effect of extracts from Lentinus edodes mycelia on dimethylnitrosamine-induced liver injury. Biol Pharm Bull . 2004;27(12):1957-1960.
52. Zhou LD, Zhang QH, Zhang Y, Liu J, Cao YM. The shiitake mushroom-derived immuno-stimulant lentinan protects against murine malaria blood-stage infection by evoking adaptive immune-responses. Int Immunopharmacol . 2009;9(4):455-462.
53. Kaneko Y, Chihara G. Potentiation of host resistance against microbial infections by lentinan and its related polysaccharides. Adv Exp Med Biol . 1992;319:201-215.
54. Guo Z, Hu Y, Wang D, et al. Sulfated modification can enhance the adjuvanticity of lentinan and improve the immune effect of ND vaccine. Vaccine . 2009;27(5):660-665.
55. Hearst R, Nelson D, McCollum G, et al. An examination of antibacterial and antifungal properties of constituents of Shiitake ( Lentinula edodes ) and oyster ( Pleurotus ostreatus ) mushrooms. Complement Ther Clin Pract . 2009;15(1):5-7.
56. Tochikura T, Nakashima H, Kaneko Y, Kobayashi N, Yamamoto N. Suppression of human immunodeficiency virus replication by 3′-azido-3′-deoxythymidine in various human hematopoietic cell lines in vitro: augmentation of the effect by lentinan. Jpn J Cancer Res . 1987;78(6):583-589.
57. Yoshida O, Nakashima H, Yoshida T, et al. Sulfation of the immunodulating polysacchraride lentinan: a novel strategy for antivirals to human immunodeficiency virus (HIV). Biochem Pharmacol . 1988;37(15);2887-2891.
58. Gordon M, Bihari B, Goolsby E, et al. A placebo-controlled trial of the immune modulator, lentinan, in HIV-positive patients: a phase I/II trial. J Med . 1998;29:305-330.
59. Ngai PHK, Ng TB. Lentin, a novel and potent antifungal protein from shitake mushroom with inhibitory effects on activity of human immunodeficiency virus-1 reverse transcriptase and proliferation of leukemia cells. Life Sci . 2003;73(26):3363-3374.
60. Chibata I, Okumura K, Takeyama S, et al, Lentinacin: a new hypocholesterolemic substance in Lentinus edodes . Experientia . 1969;25:1237-1238.
61. Rivera A, Benavides OL, Rios-Motta J. (22E)-Ergosta-6,22-diene-3beta,5alpha,8alpha-triol: a new polyhydroxysterol isolated from Lentinus edodes (Shiitake). Nat Prod Res . 2009;23(3):293-300.
62. Chihara G. Recent progress in immunopharmacology and therapeutic effects of polysaccharides. Dev Biol Stand . 1992;77:191-197.
63. Aalto-Korte K, Susitaival P, Kaminska R, Mäkinen-Kiljunen S. Occupational protein contact dermatitis from shiitake mushroom and demonstration of shiitake-specific immunoglobulin E. Contact Dermatitis . 2005;53(4):211-213.
64. Suzuki K, Tanaka H, Sugawara H, et al. Chronic hypersensitivity pneumonitis induced by Shiitake mushroom spores associated with lung cancer. Intern Med . 2001;40(11):1132-1135.
65. Mak RK, Wakelin SH. Shiitake dermatitis: the first case reported from a European country. Br J Dermatol . 2006;154(4):800-801.
66. Levy AM, Kita H, Phillips SF, et al. Eosinophilia and gastrointestinal symptoms after ingestion of shiitake mushrooms. J of Allergy Clin Immunol . 1998;101(5):613-620.

Copyright © 2009 Wolters Kluwer Health

Hide
(web3)