Lentinan

What Is It?

Lentinan is a glucan derived from the common shiitake mushroom, Lentinus edodes. Since 1985, it has been used in Japan as an adjuvant for stomach cancer therapy$^{1}$ and is known for its immunomodulatory activity$^{2}$. Many pharmaceuticals are formulated from lentinan$^{1}$, as it has demonstrated immune-stimulating effects$^{3}$. Most importantly, however, lentinan has been investigated as a potential cancer-fighting nutrient, demonstrating potential efficacy in clinical trials against gastric, prostate, and liver cancers.

What Are Its Other Names?

Lentinus edodes, the only source of lentinan, is also referred to as Shiitake, Hua gu, Snake butter, Forest mushroom, Sun’s soup, and Pasania fungus$^{4}$.

What Foods Have It?

Shiitake mushrooms are the sole food source of lentinan, and different studies have found the nutrient content to be 15.5 mg in 100 g of fresh fruit bodies or 12.8 mg of lentinan per gram of dry weight mushroom. Note that lentinan content is affected by temperature, and one study found that lentinan content decreased from 12.8 mg/g dry weight to 3.7 mg/g over 7 days at 20°C, whereas it only decreased to 9.3 mg/g at 5°C, and only slightly dipped at 1°C. This is because the activity of glucanase, the enzyme in mushrooms that degrades lentinan, is upregulated at 20°C. Thus, it is important to note that the lentinan content of shiitake mushrooms is greatly impacted by temperature$^{5}$. 

What Are Its Main Benefits?

Antibacterial Activity Lentinan was shown to have antibacterial activity against Mycobacterium tuberculosis$^{6}$, the bacterium that causes a serious lung infection, and Listeria monocytogenes$^{7}$, which can cause a food-borne illness called listeriosis. This was shown in animal studies, whereby it improved the bacteria-killing activities of tissue-resident immune cells called macrophages.  Treating Various Diseases Lentinan has been shown to have immunomodulating effects against malaria by enhancing the T cell response against the plasmodium, the microscopic organism responsible for malaria infections$^{8}$. In addition, in a phase II placebo-controlled study in 107 HIV patients, lentinan was used in conjunction with didanosine (a drug used to treat HIV) and it was found to lead to a significant increase in plasma counts of CD4+ T cells, the primary cell type impacted by an HIV infection$^{9}$. Treating Cancer  Many clinical trials have demonstrated lentinan’s efficacy at treating colorectal, gastric, lung, and ovarian cancer$^{1}$. Furthermore, chemotherapy in conjunction with lentinan showed better results than chemotherapy alone, and the nutrient improved chemotherapy-induced leukopenia (low white blood cell count), thrombocytopenia (low platelet count), and vomiting, in addition to improving the overall quality of life and physical health of patients with breast, colorectal, gastric, hepatic intestinal, and lung cancers$^{10}$.  In a multicentre clinical study on patients with colorectal cancer, oral lentinan was found to suppress the adverse effects of chemotherapy and improve quality of life markers. Lentinan was also found in other studies to improve the 1-year survival rate, median survival, and quality of life in gastric cancer and esophageal carcinoma patients$^{11}$. Lentinan is also often used as an adjuvant in stomach cancer therapy in Japan$^{1}$.

What Are Its Main Drawbacks?

Some drawbacks have been associated with lentinan being used as an anticancer nutrient, including the development of shiitake dermatitis (swelling and irritation of the skin), mild side effects with lentinan infusions, and its heat instability. In some people, the consumption of shiitake mushrooms has been associated with a rash known as shiitake dermatitis, which manifests as patterns of “whip-like”, “linear”, and erythematous (red) wheals (skin elevations) and often shows up within 1-2 days of consuming raw or undercooked shiitake mushrooms. Note that it does resolve within days or weeks and is not particularly serious$^{12}$.  A second drawback associated with lentinan has been the manifestation of mild side effects related to lentinan infusions in clinical trials. Severe reactions have been associated with short infusion times and include anaphylactoid reactions (a severe allergic reaction similar to anaphylaxis), back and leg pain, depression, rigor, fever, chills, and elevated liver enzymes$^{13}$.  Lastly, lentinan decomposes upon heating, which means that its antitumor properties are lost if the shiitake mushrooms are cooked. Thus, to wield the anticancer effects of shiitake mushrooms, they must be consumed raw, which carries with it the risk of developing shiitake dermatitis, as previously mentioned$^{13}$. 

What Are Its Mechanisms of Action?

1. Inducing Immune Activity: While lentinan exhibits no direct cytotoxicity (toxicity to cells), it stimulates the cell-killing abilities of macrophages$^{3}$, an important immune cell in the body. It enhances antibody-dependent cellular cytotoxicity, which is an important mechanism by which the body’s immune system attacks cells that bear tumor-related antigens on their surface$^{14}$. Lentinan has also been shown to act synergistically with chemotherapy in gastric cancer patients to activate complement systems through antibody-dependent cell-mediated cytotoxicity, thereby prolonging overall survival more than chemotherapy alone$^{15}$.
2. Triggering Important Signalling Pathways: Lentinan will trigger several important signalling pathways involved in reducing inflammation and combatting tumor cells in the body. Through binding to immune cell receptors known as pattern recognition receptors, such as toll-like receptors and the Dectin-1 receptor, as well as the complement receptor type 3 on the membrane of natural killer (NK) cells, macrophages, and T cells, lentinan activates the following pathways: the MAPK pathway, which regulates immune responses$^{16,17}$; the NF-KB pathway, which is important to the function of adaptive immune cells$^{16,18}$, and the Syk-PKC pathway, involved in immune cell activation$^{16,19}$. Enhancing the activity of NK cells, macrophages, and T cells is critical in combatting cancerous cells, as they recognize them as foreign cells and work to eliminate them from the body.
3. Reducing Inflammation and Oxidative Stress: Lentinan has been shown in petri dishes to attenuate the release of pro-inflammatory cytokines in response to lipopolysaccharide, or LPS, which is a component of Gram-negative bacteria responsible for triggering systemic inflammation during infections. It also reduces oxidative stress$^{20}$, which is usually responsible for cancer-promoting DNA damage.

What Are Typical Doses and Durations?

Lentinan can be introduced into the body via oral or intravenous routes. However, information about recommended dietary allowances of lentinan was not found. Note that eating raw shiitake mushrooms carries with it the risk of shiitake dermatitis but cooking them significantly reduces their lentinan content$^{12}$. With regards to orally administered lentinan for therapeutic purposes, one study used 8 g/ day of oral extract of lentinan for 6 months to treat prostate cancer$^{21}$ but yielded no significant effect on disease outcomes. With regards to intravenously administered lentinan, it is often used as an adjuvant therapy for HIV and cancer at a dose of 2 – 10 mg intravenously$^{22}$. In the clinical trials listed below, 2 mg of lentinan administered intravenously had no effect on gastric cancer outcomes, although 500 mg/day of lentinan for 18 months was shown to be effective in patients with hepatocellular carcinoma. 

Summary of Data

A total of 9 randomized clinical trials that investigated lentinan as an anticancer nutrient were identified on PubMed. Although, clinical trials investigated the effect of lentinan on outcomes for cases of existing cancer, rather than on preventing cancer. The data from the trials is summarized below.

📄 Detailed Lentinan human clinical trial study notes analyzed by Anticancer.ca

About This Article

References

1. Niego, A. G.et al.Macrofungi as a Nutraceutical Source: Promising Bioactive Compounds and Market Value. Journal of Fungi 7, 397 (2021).
2. Jafari, M. et al. Lentinan and β-glucan extract from shiitake mushroom, Lentinula edodes, alleviate acute LPS-induced hematological changes in mice. Iranian journal of basic medical sciences 26, 836–842 (2023).
3. Tizard, I. R. & Ni, Y. Carbohydrates, Immune Stimulating. inEncyclopedia of Immunology (Second Edition) (ed. Delves, P. J.) 427–431 (Elsevier, Oxford, 1998). doi:10.1006/rwei.1999.0110.
4. Lentinan Uses, Benefits & Dosage - Drugs.com Herbal Database.Drugs.com https://www.drugs.com/npp/lentinan.html(2023).
5. Minato, K., Mizuno, M., Terai, H. & Tsuchida, H. Autolysis of Lentinan, an Antitumor Polysaccharide, during Storage of Lentinus edodes, Shiitake Mushroom.J. Agric. Food Chem. 47, 1530–1532 (1999).
6. Markova, N., Michailova, L., Kussovski, V., Jourdanova, M. & Radoucheva, T. Intranasal application of lentinan enhances bactericidal activity of rat alveolar macrophages against Mycobacterium tuberculosis.Die Pharmazie - An International Journal of Pharmaceutical Sciences 60, 42–48 (2005).
7. Kupfahl, C., Geginat, G. & Hof, H. Lentinan has a stimulatory effect on innate and adaptive immunity against murine Listeria monocytogenes infection.Int Immunopharmacol6, 686–696 (2006).
8. Zhou, L., Zhang, Q., Zhang, Y., Liu, J. & Cao, Y. The shiitake mushroom-derived immuno-stimulant lentinan protects against murine malaria blood-stage infection by evoking adaptive immune-responses.International Immunopharmacology9, 455–462 (2009).
9. Gordon, M.et al.A phase II controlled study of a combination of the immune modulator, lentinan, with didanosine (ddI) in HIV patients with CD4 cells of 200-500/mm3. J Med 26, 193–207 (1995).
10. Zhang, M., Zhang, Y., Zhang, L. & Tian, Q. Chapter Thirteen - Mushroom polysaccharide lentinan for treating different types of cancers: A review of 12 years clinical studies in China. inProgress in Molecular Biology and Translational Science (ed. Zhang, L.) vol. 163 297–328 (Academic Press, 2019).
11. Wasser, S. P. Medicinal Mushrooms in Human Clinical Studies. Part I. Anticancer, Oncoimmunological, and Immunomodulatory Activities: A Review.IJM 19, (2017).
12. Mendonça, C. N. de, Silva, P. M. C. e, Avelleira, J. C. R., Nishimori, F. S. & Cassia, F. de F. Shiitake dermatitis.An. Bras. Dermatol.90, 276–278 (2015).
13. Lentinan | Memorial Sloan Kettering Cancer Center.https://www.mskcc.org/cancer-care/integrative-medicine/herbs/lentinan(2023).
14. Gómez Román, V. R., Murray, J. C. & Weiner, L. M. Chapter 1 - Antibody-Dependent Cellular Cytotoxicity (ADCC). inAntibody Fc(eds. Ackerman, M. E. & Nimmerjahn, F.) 1–27 (Academic Press, Boston, 2014). doi:10.1016/B978-0-12-394802-1.00001-7.
15. Ina, K., Kataoka, T. & Ando, T. The use of lentinan for treating gastric cancer.Anticancer Agents Med Chem 13, 681–688 (2013).
16. Jafari, M.et al.Lentinan and β-glucan extract from shiitake mushroom, Lentinula edodes, alleviate acute LPS-induced hematological changes in mice. Iranian journal of basic medical sciences 26, 836–842 (2023).
17. Dong, C., Davis, R. J. & Flavell, R. A. MAP kinases in the immune response.Annu Rev Immunol20, 55–72 (2002).
18. Liu, T., Zhang, L., Joo, D. & Sun, S.-C. NF-κB signaling in inflammation.Sig Transduct Target Ther2, 1–9 (2017).
19. Kawakami, Y.et al.A Ras activation pathway dependent on Syk phosphorylation of protein kinase C. Proceedings of the National Academy of Sciences 100, 9470–9475 (2003).
20. Murphy, E. J.et al.β-Glucan extracts from the same edible shiitake mushroom Lentinus edodes produce differential in-vitro immunomodulatory and pulmonary cytoprotective effects - Implications for coronavirus disease (COVID-19) immunotherapies. Sci Total Environ 732, 139330 (2020).
21. deVere White, R. W., Hackman, R. M., Soares, S. E., Beckett, L. A. & Sun, B. Effects of a mushroom mycelium extract on the treatment of prostate cancer.Urology60, 640–644 (2002).
22. Gordon, M.et al.A placebo-controlled trial of the immune modulator, lentinan, in HIV-positive patients: a phase I/II trial. J Med 29, 305–330 (1998).

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• Lentinan
• What Is It?
• What Are Its Other Names?
• What Foods Have It?
• What Are Its Main Benefits?
• What Are Its Main Drawbacks?
• What Are Its Mechanisms of Action?
• What Are Typical Doses and Durations?
• Summary of Data
• About This Article
• References
• Disclaimer