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Medicinal Mushrooms and Cancer

Review by Kerry Bone, FNIMH, FNHAA
The Townsend Letter - August/September 2007

The therapeutic properties of mushrooms are recognized in many countries, but particularly in China and Japan, where they are an important part of traditional Chinese Medicine (TCM). Ganoderma (in particular Ganoderma lucidum) is the most highly prized and longest-used medicinal mushroom. Its use is said to date back more than 4000 years, and worldwide sales are reported to exceed $1.5 billion per year. In China, Ganoderma is known as ling zhi or "mushroom of immortality," and this attests to a general property attributed to the medicinal mushrooms: they are life-prolonging.1

Recently, a major clinical focus for these mushrooms has been their role as adjunctive treatments for various types of cancer. Perhaps it was the association with tonic properties and longevity, or maybe it was the observation that some active components of these mushrooms (particularly the poly-saccharides) modify the immune response and help the body to fight tumor cells. Whatever the reason, the connection has been made, and the experimental and clinical evidence is steadily accumulating. This column will focus on the studies on Ganoderma, but will also briefly review some of the research on the shiitake mushroom (Lentinula edodes or Lentinus edodes).

Ganoderma

The Ganoderma lucidum fruiting body is regarded in TCM as a nourishing tonic and aphrodisiac that tonifies the qi. It is used for neurasthenia, insomnia, cough, palpitations, and debility due to prolonged sickness. There have been many legends in Chinese history linking Ganoderma to longevity.2,3 Among cultivated mushrooms, Ganoderma is unique in being only consumed as a medicinal remedy rather than as a food.4 The mushroom is bitter and indigestible (consisting of a hard matrix of chitin). As a therapy, Ganoderma is administered in powder form, as a decoction, or as a solvent-based extract/concentrate to improve its digestibility and bioavailability.5,6

Ganoderma has also been used traditionally in Japan where it is known as reishi.7 A survey conducted in Hong Kong found Ganoderma to be the third-most common herbal medicine used by pre-surgical patients.8 Key constituents include triterpene acids and poly-saccharides.3

Clinical Studies: Cancer

The results of a randomized, double-blind, placebo-controlled trial indicate that Ganoderma extract (equivalent to 90 g/day of mushroom) may play an adjunct role in the treatment of patients with advancedlung cancer. After 12 weeks of Ganoderma treatment, stable disease occurred in 35% of patients, compared to 22% in the control group. Palliative effects on cancer-related symptoms and an increase in Karnofsky performance score occurred in a greater number of patients receiving Ganoderma.9

Ganoderma extract enhanced the immune responses of patients with advanced stage cancer (mainly lung, breast, liver, colon, prostate, bladder, brain) in an uncontrolled trial of 12-weeks duration. Compared to baseline values, treatment with Ganoderma resulted in a significant increase in the mean plasma concentrations of interleukin (IL)-2, IL-6, and interferon-gamma and in the mean natural killer activity.lO Similar results wereobserved in a trial involving patients with advanced lung cancer. In addition, treatment with Ganoderma extract (equivalent to 81 g/day of mushroom) decreased plasma tumor necrosis factor-alpha in more than half the patients. Most of these patients experienced less body weight loss, chronic nausea, fatigue, insomnia, and profuse sweating.11

Treatment with Ganoderma extract for more than 12 weeks in uncontrolled trial lead to a stable disease state in 26.6%of patients with advanced solid tumors (mainly liver, lung, breast, ovary).12 In other uncontrolled trials, Ganoderma extract improved the immune function and stamina of debilitated patients and cancer patients undergoing chemo- and radiotherapies.13

Possible Mechanism of Action

The polysaccharides of Ganoderma - in particular, the beta-D-glucans - are potent stimulators of macrophages in vitro. They may induce a biological response by binding to a macrophage receptor, triggering a series of events, including activation of NF-kappaB and the release of a variety of cytokines and other mediators.14 However, it is believed that the anticancer properties of Ganoderma are contained in the diversity of chemical constituents. The triterpenes also possess multiple bioactivities, including immunomodulating, antioxidative, and antitumor effects.15 In fact, the triterpenes appear to have a stronger direct antitumor activity than the polysaccharides.16

Ganoderma was the most active cytotoxic mushroom to cancer cells of 58 species tested. Inhibition of proliferation has been shown in various cancer cell lines in vitro, including lymphocytic leukemia, lung carcinoma, hepatoma, and breast; prostate, and bladder cancer cells.15 Several studies have correlated the tumoricidal effects of Ganoderma with the regulation of cancer cell cycling and signaling.15,17 Antiangiogenic and antimetastatic properties have additionally been demonstrated in several experimental models.15,18 The triterpenes in Ganoderma also have exerted antitumor-promoting effects in vitro.19

Clinical Studies: Tonic and Immune Activity

Ganoderma extract (equivalent to 81 g/day of mushroom) was significantly superior to placebo in reducing physical and mental fatigue in a randomized, double-blind trial of Chinese patients with neurasthenia.20 Treatment with Ganoderma restored endothelial cell cytotoxicity and immunocirculatory balance to normal and successfully suppressed proteinuria in an uncontrolled trial involving 14 nephrotic patients with moderately impaired renal function. Following treatment with Ganoderma extract (900-1125 mg/day), vitamin C (1-3 g/day), and vitamin E (400-800 IV/day), other parameters of renal function were improved (creatinine clearance and fractional excretion of magnesium)21 In an earlier pilot study, Ganoderma also suppressed proteinuria in nephrotic patients.22 In both trials, vasodilators were prescribed as standard treatment.

In a double-blind, placebo-controlled trial, Ganoderma (4.1 g/day of mushroom, for four weeks) reduced systolic and diastolic blood pressure in patients with stage II primary hypertension who were unresponsive to angiotensin-converting enzyme inhibitors.23

Twenty-five percent of patients with chroni hepatitis B who randomly received Ganoderma for 12 weeks responded� by reducing hepatitis B e antigen and hepatitis B viral DNA, compared to four percent in the placebo group. After a follow up of a further 13 weeks, of those receiving Ganoderma, 33% had nor aminotransferase values, and 13% had cleared hepatitis B surface antigen from serum, although this did n occur in the placebo group.24 In a small, uncontrolled trial, one month of treatment with Ganoderma improved liver function parameters in patients with hepatitis B.5

Ganoderma extract (equivalent to 36-72 g/day of dry mushroom) alleviated pain in two patients with postherpetic neuralgia and two patients with herpes zoster infection.25

In China, a decoction of Ganoderma (per do 100 g/600 mL), in addition to standard treatment provided a better outcome in patients with mushroom poisoning compared to those receiving only standard treatment.26 In a randomized, double-blind trial involving patients with confirmed coronary heart disease treatment with Ganoderma significantly decreased blood pressure and serum cholesterol from baseline. In the placebo group, these parameters were unchanged. Ganoderma treatment produced a higher percentage of improvement of symptoms and a lower percentage of abnormal electrocardiograms compared to those receiving placebo.27 Symptoms improved hypertensive patients who received Ganoderma extract, (equivalent to 5.2 g/day of dry mushroom). No changes were observed in the placebo group.5 In uncontrolled trials conducted in China, Ganoderma has been administered to treat insomnia leukopenia, acute altitude sickness, chronic bronchitis and insomnia.2,28

Shiitake

The shiitake mushroom was renowned in China and Japan as a food and medicine for thousands of years.7 In Japan and China, medicinal dishes (yakuzen) are garnished with mushrooms, including shiitake.29 The emperors of China are said to have eaten the mushroom in great quantities to slow the onset of old age. In Japanese traditional medicine (Kanpo), shiitake improves qi.30 In TCM, it is strengthening a restorative.6

Shiitake contains protein, carbohydrates (largely dietary fiber), vitamins, minerals, and low levels of lipids. A polysaccharide in shiitake receiving much research attention is lentinan, a beta-glucan.31 The lentinan content of shiitake varies according to growing methods and conditions, and storage. Prior to storage at 20�C, a content of 1.3% (dry weight) has been found.32,33

Shiitake and lentinan have shown antitumor activity when administered orally in experimental models. Lentinan appears to modulate the systemic immune function through stimulation of T cells, especially helper cells.34,35,36,37

Clinical Studies

Japanese researchers suggested in the mid-1980s that lentinan could be effective when taken orally. Patients with an immune deficiency condition characterized by low natural killer cell activity improved after treatment with lentinan. Patients received intravenous lentinan in hospital and took maintenance doses orally as outpatients.38 Lentinan is often given as part of a combination therapy for cancer in addition to conventional cytotoxic drugs.39,40 Oral doses of powdered shiitake (1.5 g) increased the levels of helper T cells in healthy volunteers. In those taking placebo, the levels were unchanged.30

Conclusions

These herbs would complement each other in a formulation providing immune-enhancing, tonic, and nourishing activity particularly applicable to supporting cancer patients. Based on the clinical data, the key modern uses for these mushrooms are as follows:

  • as an adjuvant complementary therapy for cancer,
  • to counteract the immunosuppressive and debilitating effects of conventional cancer treatments,
  • in states of weakened or suppressed immunity such as post-viral syndromes, HIV infection and autoimmune diseases,
  • in chronic fatigue syndrome, debilitated conditions.
Notes:
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2. Chang HM, But PP (eds). Pharmacology and Applications of Chinese Materia Medica. Singapore: World Scientific; 1987.
3. Bensky D, Clavey S, Stoger E. Chinese Herbal Medicine: Materia Medica. 3rd Edition. Seattle: Eastland Press; 2004.
4. Chen JJ, Shih NL. Myth of linzhi, the mushroom of immortality: a potential antitumor/antiaging agent in humans. Acta Cardiol Sin. 2002; 18: 113-114.
5. American Herbal Pharmacopoeia. Reishi Mushroom - Ganoderma lucidum: Standards of Analysis, Quality Control, and Therapeutics. Santa Cruz, California: American Herbal Pharmacopoeia; September 2000.
6. Smith J, Rowan N, Sullivan R. Medicinal Mushrooms: Their Therapeutic Properties and Current Medical Usage with Special Emphasis on Cancer Treatments. London: Cancer Research UK; 2002.
7. Hobbs C. Medicinal Mushrooms: An Exploration of Tradition, Healing & Culture. 2nd Edition. Santa Cruz, California: Botanica Press; 1986.
8. Lee A, Aun C, Chui PT. Abstract Book of the Annual Scientific Meeting of Hong Kong College of Anaesthesiologists. November 2002, Hong Kong.
9. Gao Y, Dai X, Chen G, et al. A randomized, placebo-controlled, multicenter study of Ganoderma lucidum (W.Curt.:Fr) Lloyd (Aphylloromycetidae) polysaccharides (Ganopoly R) in patients with advanced lung cancer. Int J Medicinal Mushrooms. 2003; 5: 369-381.
10. Gao Y, Zhou S, Jiang W, et al. Effects of Ganopoly: (a ganoderma lucidum polysaccharide extract) on the immune functions in advanced-stage cancer patients. Immunol Invest. 2003;32(3):201-216.
11.Gao Y, Tang W, Dai X, et al. Effects of water-soluble Ganoderma lucidum polysaccharides on the immune functions of patients with advanced lung cancer. J Med Food. 2005; 8(2): 159-168.
12. Gao Y, Zhou S, Chen G, et al. A Phase I/II study of a Ganoderma lucidum extract (Ganopoly) in patients with advanced cancer. Int J Medicinal Mushrooms. 2002; 4: 207-214.
13. McKenna DJ, Jones K, Hughes K, et al. Botanical Medicines: The Desk Reference for Major Herbal Supplements. 2nd Edition. New York: Haworth Herbal Press; 2002.
14. Gao Y, Chan E, Zhou S. Immunomodulating activities of Ganoderma, a mushroom with medicinal properties. Food Rev Int. 2004; 20(2): 123-161.
15. Yuen JWM, Gohel MDI. Anticancer effects of Ganoderma lucidum: a review of scientific evidence. Nutr Cancer. 2005; 53(1): 11-17.
16. Xie JT, Wang CZ, Wicks S, et al. Ganoderma lucidum extract inhibits proliferation of SW 480 human colorectal cancer cells. Exp Oncol. 2006; 28(1): 25-29.
17. Jiang J, Clivova V, Sliva D. Ganoderma lucidum inhibits proliferation of human breast cancer cells by down-regulation of estrogen receptor and NF-kappaB signaling. Int J Oncol. 2006; 29(3):695-703.
18. Stanley G, Harvey K, Slivova V, et al. Ganoderma lucidum suppresses angiogenesis through the inhibition of secretion of VEGF and TGF-betal from prostate cancer cells. Biochem Biophys Res Commun. 2005; 330(1): 46-52.
19. Akihisa T, Nakamura Y, Tagata M, et al. Anti-inflammatory and anti-tumor-promoting effects of triterpene acids and sterols from the fungus Ganoderma lucidum. Chem Biodivers. 2007; 4(2):224-231.
20. Tang W, Gao Y, Chen G, et al. A randomized, double-blind and placebo-controlled study of a Ganoderma lucidum polysaccharide extract in neurasthenia. J Med Food. 2005; 8(1): 53-58.
21. Futrakul N, Panichakul T, Butthep P, et al. Ganoderma lucidum suppresses endothelial cell cytotoxicity and proteinuria in persistent proteinuric focal segmental glomerulosclerosis (FSGS) nephrosis. Clin Hemorheol Microcirc. 2004;31(4): 267-272.
22. Futrakul N, Boongen M, Tosukhowong P, et al. Treatment with vasodilators and crude extract of Ganoderma lucidum suppresses proteinuria in nephrosis with focal segmental glomerulosclerosis. Nephron. 2002; 92(3): 719-720.
23. Nimmi H, Xiu RJ, Sawada T, et al. Microcirculatory Approach to Asian Traditional Medicine. New York: Elsevier Science; 1996.
24. Gao Y, Zhou S, Chen G, et al. A Phase I/II study of a Ganoderma lucidum extract in patients with chronic hepatitis B. Int J Medicinal Mushrooms. 2002; 4: 321-327.
25. Hijikata Y, Yamada S. Effect of Ganoderma lucidum on postherpetic neuralgia. Am J Chin Med. 1998; 26(3-4): 375-381.
26. Xiao GL, Liu FY, Chen ZH. [Clinical observation on treatment of Russula subnigricans poisoning patients by Ganoderma lucidum decoction] Zhongguo Zhong Xi Yi Jie He Za Zhi. 2003; 23(4): 278-280 [Article in Chinese].
27. Gao Y, Lan J, Dai X, et al. A Phase I/II study of ling zhi mushroom ganoderma lucidum (w.curt.:fr)Lloyd (aphyllophoromycetideae) extract in patients with type ii diabetes mellitus. Int J Medicinal Mushrooms. 2004; 6: 327-334.
28. Huang KC. The Pharmacology of Chinese Herbs. Boca Raton, Florida: CRC Press; 1993.
29. Mizuno T, Sakai T, Chihara G. Health foods and medicinal usages of mushrooms. Food Rev Int. 1995; 11(1): 69-81.
30. Jones K. Shiitake: The Healing Mushroom. Rochester, Vermont: Healing Arts Press; 1995.
31. Breene WM. Nutritional and medicinal value of specialty mushrooms. J Food Protect. 1990; 53(10): 883-894.
32. Minato K, Mizuno M, Terai H, et al. Autolysis of lentinan, an antitumor polysaccharide, during storage of lentinus edodes, shiitake mushroom. J Argic Food Chem. 1999; 47(4): 1530-1532.
33. Brauer D, Kimmons T, Phillips M. Effects of management options on the yield and high molecular weight polysaccharide content of shiitake (lentinus edodes) mushrooms. J Argic Food Chem. 2002; 50(19):5333-5337.
34. Borchers AT, Stern JS, Hackman RM et al. Mushrooms, tumors, and immunity. Proc Soc Exp Biol Med. 1999; 221(4):281-293.
35. Jong SC, Birmingham JM. Medicinal and therapeutic value of the shiitake mushroom. Adv Appl Microbiol. 1993; 39: 153-184.
36. Hanaue, H, Tokuda Y, Machimura Y. Effects of oral lentinan on T-cell subsets in peripheral venous blood. Clin Ther 1989; 11(5): 614-622.
37. Ng ML, Yap AT. Inhibition of Human Colon Carcinoma Development by Lentinan from Shiitake Mushrooms (Lentinus edodes). J Altern Complement Med 2002; 8(5): 581-589.
38. James JS. Shiitake, Lentinen, and AIDS/ARC. AIDS Treat News 1986; 19: 99- 104.
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