Medicinal Mushrooms (PDQ®)–Health Professional Version
Medicinal mushrooms have been used for hundreds of years, mainly in Asian countries, for treatment of infections. More recently, they have also been used in the treatment of pulmonary diseases and cancer. Medicinal mushrooms have been approved adjuncts to standard cancer treatments in Japan and China for more than 30 years and have an extensive clinical history of safe use as single agents or combined with radiation therapy or chemotherapy.
More than 100 species of medicinal mushrooms are used in Asia. Some of the more commonly used species include the following:
- Ganoderma lucidum (reishi).
- Trametes versicolor or Coriolus versicolor (turkey tail).
- Lentinus edodes (shiitake).
- Grifola frondosa (maitake).
Studies have examined the effects of mushrooms on immune response pathways and on direct antitumor mechanisms. The immune effects are mediated through the mushroom's stimulation of innate immune cells, such as monocytes, natural killer cells, and dendritic cells. The activity is generally considered to be caused by the presence of high-molecular-weight polysaccharides (beta-glucans) in the mushrooms, although other constituents may also be involved. Clinical trials in cancer patients have demonstrated that G. lucidum products are generally well tolerated.
Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.
Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.
- Jin X, Ruiz Beguerie J, Sze DM, et al.: Ganoderma lucidum (Reishi mushroom) for cancer treatment. Cochrane Database Syst Rev 6: CD007731, 2012. [PUBMED Abstract]
Turkey Tail and Polysaccharide-K
Turkey tail is a woody bracket polypore fungus that grows on dead logs worldwide. The scientific name of turkey tail is Trametes versicolor (L.) Lloyd, although it has been known by other names, notably Coriolus versicolor (L. ex Fr.) Quel. It is known as Yun Zhi in traditional Chinese medicine and Kawaratake (roof tile fungus) in Japan. The name turkey tail refers to its concentric rings of brown and tan, which resemble the tail feathers of a turkey. There are many other species of Trametes, some of which are difficult to distinguish from turkey tail. Internal transcribed spacer sequences alone have been found inadequate to distinguish turkey tail from other species of Trametes, so additional molecular characters are required for that task. Another Trametes species used primarily in China is Trametes robiniophila Murr, also known as Huaier.
The fungus has been used in traditional Chinese medicine for many years to treat pulmonary diseases.[2,3] A purified hot water extract prepared from the cultivated fungal mycelium has been used in Japan for its immunomodulatory effects as an adjuvant treatment for cancer.[4-6] Polysaccharide-K (PSK) or krestin, from the mushroom T. versicolor, is an approved mushroom product used for cancer treatment in Japan. PSK is a proprietary formulation from the Kureha Corporation. PSK has been used as an adjunctive cancer treatment in thousands of patients since the mid-1970s. The safety record for PSK is well established in Japan. Few adverse events have been reported in patients treated with PSK. Polysaccharopeptide (PSP) is another extract from T. versicolor produced in China.
The best known constituent of turkey tail is the glycoprotein mixture known as PSK. PSK is not a homogeneous substance, with a range of molecular weights averaging 9.4 kDa (range 5–300 kDa). The glycoprotein molecules are composed of a main chain beta-(1,4) glucan with beta-(1,3)– and beta-(1,6)–linked side chains. Small amounts of galactose, mannose, and arabinose have also been detected in the hydrolysate. Between 25% and 38% of the mass comes from a covalently linked protein whose amino acid composition has been reported.
PSK radiolabeled with carbon C-14 has been used to study the oral bioavailability and distribution of PSK in mice, rats, and rabbits. A fraction of the dose appears to be orally absorbed, more or less intact, and is excreted in bile over several hours. However, most of the radiolabeled dose is found in exhaled air, suggesting that the digestion of PSK may occur in the gut or the metabolism of absorbed PSK may occur somewhere else in the body. A monoclonal antibody (specific for PSK) that neutralizes PSK's antitumor effects has been developed. It has been used to validate the presence of PSK in implanted tumors.
PSP, a very similar substance, has also been purified from a different strain of turkey tail; PSP and PSK differ somewhat in sugar composition.
A lipid component of PSK has been separated by lipase treatment and found to have toll-like receptor 2 agonist activity, synergistic with the protein-bound beta-glucan. The lipid component was primarily linoleic acid, with smaller amounts of other fatty acids.
Since the earliest reports of clinical benefits, other investigators have sought to define the mechanism of PSK’s beneficial action. One group hypothesized that T-cell dysfunction, including apoptosis of peripheral blood T cells, commonly occurs in patients receiving chemotherapy. They postulated that reversal of T-cell dysfunction induced by chemotherapy could reduce the adverse effects or enhance the antitumor effect. PSK is reported to enhance natural killer (NK) cell and T-cell activities by upregulation of interleukin-2 or interferon-gamma. Twenty patients with curatively resected stage III gastric cancer were randomly assigned to receive adjuvant therapy with the second-generation dihydropyrimidine dehydrogenase–inhibitory oral fluoropyrimidine S-1 alone (n = 10) or S-1 plus PSK (n = 10). At 5 weeks after adjuvant therapy, T-cell apoptosis was significantly higher in the S-1–alone group than in the S-1–plus-PSK group, leading the authors to conclude that PSK could partially prevent the T-cell apoptosis induced by S-1.
Another group of investigators studied the effect of PSK added to tegafur/uracil (UFT) chemotherapy compared with that of UFT alone. Baseline immune parameters were comparable in the two groups. However, CD57-positive T cells decreased more significantly after surgery for patients treated with PSK than for those in the control group (P = .0486). These investigators had previously noted that a high CD57-positive cell count was an indicator of poor prognosis in patients with advanced gastric cancer, leading them to suggest that PSK may improve overall survival (OS) partly by inhibiting CD57-positive T cells.
Noting that hosts become immunocompromised at the time of tumor progression and that decreased expression of major histocompatibility complex (MHC) class I by the tumor is one mechanism that allows it to evade destruction by cytotoxic T lymphocytes, investigators conducted a retrospective study to evaluate the expression of MHC class I by immunohistochemical staining in the primary lesions of patients with stage II or stage III gastric cancer. They analyzed data from 349 patients who had undergone adjuvant therapy (after curative resection) between 1995 and 2008; 225 patients received adjuvant chemotherapy with an oral fluoropyrimidine alone, while 124 patients received adjuvant chemotherapy plus PSK 3 g/d. Although this was not a randomized trial, baseline characteristics of the patients were well matched. The mean duration of follow-up was 49 months. Three-year recurrence-free survival (RFS) rates were the same for both groups (60% for the PSK group and 62% for the chemotherapy-only group). For MHC expression–negative cases, the 3-year RFS rates were 65% for the PSK group and 50% for the chemotherapy-only group; the difference was not considered significant. For 82 MHC expression–negative patients with lymph node status of pN2 or greater, the RFS rates were 65% for the PSK group and 34% for the chemotherapy-only group—a significant difference with no P value offered. The authors concluded that PSK adjuvant immunotherapy may be effective in MHC class I–negative patients with advanced lymph node metastasis of pN2 or greater.
While the mechanism of action for PSK in general and in colorectal cancer specifically is not clearly defined, the potential activity of PSK as an immunomodulatory adjunct to chemoradiation therapy in rectal cancer has been studied. Thirty patients with stage II or III rectal cancer who were treated with S-1 and external-beam radiation therapy were randomly assigned to receive either the standard regimen or standard regimen plus PSK. A number of cellular and humoral immune parameters were tested. An increase in peripheral blood NK cells after therapy was observed in the PSK-treated group compared with the control group. Immunosuppressive acidic protein (IAP) levels have been reported to be elevated in cancer patients and correlated to cancer progression and prognosis. In the study, a more-marked decrease in IAP level was observed in patients treated with PSK than in those treated in the control group. In addition, cytotoxic T cells increased in the peritumoral mucosa and normal mucosa within the radiation field in the PSK-treated group. The authors of the study concluded that PSK treatment may promote local tissue immunity within the radiation field.
One review included preclinical studies conducted in lung cancer models using either PSK or other T. versicolor preparations. Data from the 15 preclinical studies supported the anticancer effects of PSK by way of immunomodulation and potentiation of immune surveillance. In animal models, direct antitumor effects resulted in reduced tumor growth and metastases.
Gastric cancer is the most common malignancy diagnosed in Korea. Investigators in Korea performed a retrospective analysis of survival in patients who received PSK in addition to chemotherapy and in those who received chemotherapy only (control group). Unfortunately, the chemotherapy regimens differed in that the PSK patients were treated with fluorouracil and mitomycin-C (207 patients), while the controls received fluorouracil with doxorubicin-based chemotherapy (103 patients), introducing a potential bias in the interpretation of the results. Patients with all stages of gastric cancer were included in the analysis. Overall, there was no difference between groups in 5-year disease-free survival (DFS) or progression-free survival (PFS) rates. In a subgroup analysis, PSK recipients with stage IB or stage II disease showed a superior 5-year survival (84.4% vs. 67.6%; P = .019), but no significant benefit was observed in patients with higher-stage disease.
Another retrospective analysis of nonrandomized data evaluated 254 patients with gastric carcinoma undergoing curative surgery with postoperative adjuvant treatment in Japan. Researchers compared 139 patients who received chemotherapy alone with 115 patients who received chemotherapy plus PSK. There were no significant differences between groups in patient demographics or tumor characteristics at baseline. There were no differences between groups in 5-year RFS rates (52.7% in the PSK group and 52.7% in the control group) or 5-year OS rates (57.1% in the PSK group and 58.3% in the control group). In a subset analysis of patients with more than seven involved lymph nodes (pN3), the 5-year OS rate was significantly higher in the PSK group (47.8%) than that in the control group (22.8%; P = .0317). Hence, these results contradict the findings from the Korean analysis.
A study published in 1994 first suggested the clinical benefit of adjuvant PSK for patients who underwent curative resection of gastric cancer in Japan. Investigators randomly assigned 262 patients who had undergone curative gastrectomy to receive either standard treatment with intravenous mitomycin and oral fluorouracil, or chemotherapy plus protein-bound PSK. Patients were monitored for 5 to 7 years. PSK improved both the 5-year DFS rate (70.7% vs. 59.4%; P = .047) and 5-year survival rate (73.0% vs. 60.0%; P = .044), compared with the standard treatment group. Treatment with PSK was well tolerated, with good compliance. The authors concluded that PSK should be added to standard chemotherapy for gastric cancer patients who undergo curative gastrectomy.
A 2007 meta-analysis included 8,009 patients from eight randomized controlled trials (RCTs) of adjuvant PSK in patients after curative resection of gastric cancers: 4,037 patients received PSK with chemotherapy, and 3,972 patients received the same chemotherapy alone. The OS hazard ratio was 0.88 (95% confidence interval [CI], 0.79–0.98; P = .018), indicating improved survival with the addition of PSK, and with no significant heterogeneity between the treatment effects observed in the different studies. The three trials with the best quality supported the findings from the eight studies. The authors concluded that PSK was effective as adjuvant immunotherapy for patients with gastric cancer and suggest that this improvement may well be both statistically and clinically significant.
One other large study not included in this meta-analysis was a Japanese multicenter comparative trial of adjuvant chemotherapy versus adjuvant chemotherapy and PSK involving 751 patients undergoing curative resection, conducted from 1978 to 1981. Patients were randomly assigned to receive either chemotherapy with mitomycin-C plus oral tegafur (also known as futraful) with (n = 377) or without (n = 374) PSK 3 g/d. After reviewing 20 years of data, the investigators stratified patients on the basis of the ratio of their granulocytes to lymphocytes (G/L), believing that G/L ratios above 2.0 would predict responders. The 5-year OS rates were 67.9% in the PSK group and 61.8% in the control group (P = .053). In the subset of 364 patients with G/L ratios above 2.0, 5-year survival rates were 68.7% in the PSK group and 55.4% in the control group (P = .007). Because the G/L ratio was not related to stage, the authors suggested that the G/L ratio may be a host-dependent factor and might be useful to predict who might respond best to adjuvant PSK.
Finally, another small study has been reported since the meta-analysis. Patients received either oral UFT 300 mg/d or UFT plus PSK 3 g/d for at least 1 year after undergoing gastric resection for stage II or stage III gastric cancer. The 3-year survival rate was 62.2% in the 10 patients who received PSK and 12.5% in the 11 patients who received UFT alone (P = .038).
A U.S. National Institutes of Health-funded phase I clinical study that used a product containing T. versicolor mycelium grown on rice, which was then freeze-dried and heated, resulted in a statistically significant increase in CD8+ cytotoxic T cells (P = .0003), CD19+ B cells (P = .0334) and NK cells (P = .043) in a dose-dependent manner in breast cancer patients.
A retrospective study of the survival of 63 patients with colorectal cancer who were older than 70 years and treated with UFT with or without PSK included 24 patients who received UFT plus PSK. The 3-year relapse-free survival rates were 76.2% in the PSK group and 47.8% in the UFT-only group (control), and the 3-year OS rates were 80.8% in the PSK group and 52.8% in the control group.
One study analyzed outcomes from 101 patients at a single institution in Japan who had Dukes B or Dukes C colorectal cancer and were treated with UFT or UFT plus PSK for 24 months after curative surgery. These patients were monitored for up to 10 years after surgery. The 10-year survival was significantly better for patients treated with PSK, with a hazard ratio of 0.3.
Clinical studies of PSK in colorectal cancer have shown reduction in recurrence and improvement in OS with adjuvant use.
A meta-analysis of randomized, centrally assigned, prospective clinical trials of adjuvant therapy with PSK published between 1980 and 2004 identified three clinical trials that met selection criteria covering 1,094 patients. Combining the data from all three trials, the researchers found that the estimated odds ratio (OR) for the following:
- The 5-year DFS was 0.72 (95% CI, 0.58–0.90; P = .003, favoring PSK).
- The 5-year OS was 0.71 (95% CI, 0.55–0.90; P = .006, favoring PSK).
Thirty-one reports of 28 studies were included in a systematic review of PSK in lung cancer:
- Seventeen preclinical studies.
- Five nonrandomized controlled trials.
- Six RCTs.
All five nonrandomized controlled trials reported improved median survival with the use of PSK in combination with conventional radiation therapy and/or chemotherapy. PSK 3 g/d with concurrent chemotherapy was used in all RCTs, and all six studies showed benefit for at least one of the following endpoints:
|Reference||Type of Study, Product, and Dose||Condition Treated||No. of Patients Enrolled; Treated; Placebo or No Treatment Controlb||Strongest Benefit Reported||Concurrent Therapy||Level of Evidence Scorec|
|G/L = granulocyte to lymphocyte count; OR = odds ratio; PSK = polysaccharide-K; RCT = randomized controlled trial; UFT = tegafur/uracil.|
|aRefer to text and the NCI Dictionary of Cancer Terms for additional information and definition of terms.|
|bNumber of patients treated plus number of patient controls may not equal number of patients enrolled; number of patients enrolled equals number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated equals number of enrolled patients who were given the treatment being studied AND for whom results were reported.|
|cStrongest evidence reported that the treatment under study has activity or otherwise improves the well-being of cancer patients. For information about levels of evidence analysis and an explanation of the level of evidence scores, refer to Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.|
|||RCT PSK (3 g/d)||Gastric cancer||751; 376; 374 (groups were stratified by G/L ratio of <2 vs. >2)||Overall 5-y survival: all patients, 67.9% (PSK) versus 61.8% (control) (P = .053); for G/L ratio ≥2: 68.7% (PSK) versus 55.4% (control) (P = .007)||Mitomycin-C plus tegafur||1iDii|
|||RCT PSK (3 g/d)||Gastric cancer||262; 124; 129||Improved survival in the treatment group was clinically significant||Mitomycin-C plus oral fluorouracil||1iDiii|
|||RCT||Gastric cancer||21; 10; 11||Survival was improved significantly in treatment group||UFT 300 mg/d starting 2 wk after surgery and continuing for 1 y or until diagnosis of tumor recurrence||1iDii|
|||Meta-analysis summarizing 48 studies||Colorectal cancer||3 trials; 1,094 patients||5-y survival: 79.0% (chemotherapy plus PSK) versus 72.2% (chemotherapy alone) (OR, 0.71; P = .006)||Mitomycin-C plus long-term administration of oral fluorinated pyrimidines||1iB|
- Carlson A, Justo A, Hibbett DS: Species delimitation in Trametes: a comparison of ITS, RPB1, RPB2 and TEF1 gene phylogenies. Mycologia 106 (4): 735-45, 2014 Jul-Aug. [PUBMED Abstract]
- Ng TB: A review of research on the protein-bound polysaccharide (polysaccharopeptide, PSP) from the mushroom Coriolus versicolor (Basidiomycetes: Polyporaceae). Gen Pharmacol 30 (1): 1-4, 1998. [PUBMED Abstract]
- Ying J, Mao X, Ma Q, et al.: Icons of Medicinal Fungi from China. Science Press, 1987.
- Tsukagoshi S, Hashimoto Y, Fujii G, et al.: Krestin (PSK). Cancer Treat Rev 11 (2): 131-55, 1984. [PUBMED Abstract]
- Cui J, Chisti Y: Polysaccharopeptides of Coriolus versicolor: physiological activity, uses, and production. Biotechnol Adv 21 (2): 109-22, 2003. [PUBMED Abstract]
- Sakagami H, Aoki T, Simpson A, et al.: Induction of immunopotentiation activity by a protein-bound polysaccharide, PSK (review). Anticancer Res 11 (2): 993-9, 1991 Mar-Apr. [PUBMED Abstract]
- Ikuzawa M, Matsunaga K, Nishiyama S, et al.: Fate and distribution of an antitumor protein-bound polysaccharide PSK (Krestin). Int J Immunopharmacol 10 (4): 415-23, 1988. [PUBMED Abstract]
- Hoshi H, Saito H, Iijima H, et al.: Anti-protein-bound polysaccharide-K monoclonal antibody binds the active structure and neutralizes direct antitumor action of the compound. Oncol Rep 25 (4): 905-13, 2011. [PUBMED Abstract]
- Quayle K, Coy C, Standish L, et al.: The TLR2 agonist in polysaccharide-K is a structurally distinct lipid which acts synergistically with the protein-bound β-glucan. J Nat Med 69 (2): 198-208, 2015. [PUBMED Abstract]
- Miller RM, Taunton J: Targeting protein kinases with selective and semipromiscuous covalent inhibitors. Methods Enzymol 548: 93-116, 2014. [PUBMED Abstract]
- Miller R, Galitsky NM, Duax WL, et al.: Molecular structures of two crystalline forms of the cyclic heptapeptide antibiotic ternatin, cyclo[-beta-OH-D-Leu-D-Ile-(NMe)Ala-(NMe)Leu-Leu-(NMe)Ala-D-(NMe)Ala-]. Int J Pept Protein Res 42 (6): 539-49, 1993. [PUBMED Abstract]
- Kono K, Kawaguchi Y, Mizukami Y, et al.: Protein-bound polysaccharide K partially prevents apoptosis of circulating T cells induced by anti-cancer drug S-1 in patients with gastric cancer. Oncology 74 (3-4): 143-9, 2008. [PUBMED Abstract]
- Akagi J, Baba H: PSK may suppress CD57(+) T cells to improve survival of advanced gastric cancer patients. Int J Clin Oncol 15 (2): 145-52, 2010. [PUBMED Abstract]
- Ito G, Tanaka H, Ohira M, et al.: Correlation between efficacy of PSK postoperative adjuvant immunochemotherapy for gastric cancer and expression of MHC class I. Exp Ther Med 3 (6): 925-930, 2012. [PUBMED Abstract]
- Sadahiro S, Suzuki T, Maeda Y, et al.: Effects of preoperative immunochemoradiotherapy and chemoradiotherapy on immune responses in patients with rectal adenocarcinoma. Anticancer Res 30 (3): 993-9, 2010. [PUBMED Abstract]
- Fritz H, Kennedy DA, Ishii M, et al.: Polysaccharide K and Coriolus versicolor extracts for lung cancer: a systematic review. Integr Cancer Ther 14 (3): 201-11, 2015. [PUBMED Abstract]
- Choi JH, Kim YB, Lim HY, et al.: 5-fluorouracil, mitomycin-C, and polysaccharide-K adjuvant chemoimmunotherapy for locally advanced gastric cancer: the prognostic significance of frequent perineural invasion. Hepatogastroenterology 54 (73): 290-7, 2007 Jan-Feb. [PUBMED Abstract]
- Tanaka H, Muguruma K, Ohira M, et al.: Impact of adjuvant immunochemotherapy using protein-bound polysaccharide-K on overall survival of patients with gastric cancer. Anticancer Res 32 (8): 3427-33, 2012. [PUBMED Abstract]
- Nakazato H, Koike A, Saji S, et al.: Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Study Group of Immunochemotherapy with PSK for Gastric Cancer. Lancet 343 (8906): 1122-6, 1994. [PUBMED Abstract]
- Oba K, Teramukai S, Kobayashi M, et al.: Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curative resections of gastric cancer. Cancer Immunol Immunother 56 (6): 905-11, 2007. [PUBMED Abstract]
- Toge T, Yamaguchi Y: Protein-bound polysaccharide increases survival in resected gastric cancer cases stratified with a preoperative granulocyte and lymphocyte count. Oncol Rep 7 (5): 1157-61, 2000 Sep-Oct. [PUBMED Abstract]
- Torkelson CJ, Sweet E, Martzen MR, et al.: Phase 1 Clinical Trial of Trametes versicolor in Women with Breast Cancer. ISRN Oncol 2012: 251632, 2012. [PUBMED Abstract]
- Yoshitani S, Takashima S: Efficacy of postoperative UFT (Tegafur/Uracil) plus PSK therapies in elderly patients with resected colorectal cancer. Cancer Biother Radiopharm 24 (1): 35-40, 2009. [PUBMED Abstract]
- Sakai T, Yamashita Y, Maekawa T, et al.: Immunochemotherapy with PSK and fluoropyrimidines improves long-term prognosis for curatively resected colorectal cancer. Cancer Biother Radiopharm 23 (4): 461-7, 2008. [PUBMED Abstract]
- Sakamoto J, Morita S, Oba K, et al.: Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curatively resected colorectal cancer: a meta-analysis of centrally randomized controlled clinical trials. Cancer Immunol Immunother 55 (4): 404-11, 2006. [PUBMED Abstract]
Reishi (Ganoderma lucidum)
Ganoderma is a genus of woody polypore fungi which grow on live trees. In the Chinese Pharmacopeia, the official species are Ganoderma lucidum (Leyss. ex Fr.) P. Karst and Ganoderma sinense Zhao, Xu et Zhang. Another commonly encountered species is Ganoderma lingzhi Wu, Cao et Dai. In traditional Chinese medicine, the fungi are collectively known as Ling Zhi; in Japan, they are known as Reishi. In China, G. lucidum is known as Chizhi and G. sinense is known as Zizhi.
Recent molecular taxonomic and chemical studies have made it clear that the originally described European species G. lucidum and the East Asian medicinal species are not identical.[1-5] The newly accepted name for the East Asian species traditionally called G. lucidum is Ganoderma sichuanense. However, most research worldwide has been published under the name G. lucidum. This includes the full genome sequence of G. lucidum. There are many other species of Ganoderma, which are difficult to distinguish from the medicinal species.
Ganoderma has a very long history in East Asia as a medicinal mushroom dating back to the Chinese materia medica “Shen Nung Ben Cao Jing,” written between 206 BC and 8 AD. It was considered a superior tonic for prolonging life, preventing aging, and boosting qi. It has been associated with royalty, perhaps due to its rarity in the wild. It was also revered in Japanese culture. It is used by contemporary Chinese physicians to support immune function in patients undergoing chemotherapy or radiation therapy for cancer, among other uses. In some parts of the world (e.g., Shanghai), cancer patients very commonly use supplements containing Ganoderma lucidum. The development of improved Ganoderma products is currently under way using biotechnological processes.
Among the biologically active components of G. lucidum are triterpenoids, polysaccharides, lipids, and proteins.[10-12] Most laboratory research studies have utilized G. lucidum products obtained via any of several extraction processes, which produce products that contain a mixture of two or more of these molecular species. This lack of purity of the products under study may account for some of the overlap of biological activities attributed to the individual components.
The best-studied Ganoderma polysaccharides possess mostly 1,3- and 1,4-glycosidic linkages, which are of high molecular weight. Beta-glucans are known to bind to the complement receptor CR3. The activity is considered to be immunomodulatory in nature, similar to many other medicinal fungi. It has recently been pointed out that Ganoderma products derived from mycelium grown on different grain substrates contain large amounts of alpha-glucans derived from the substrate, compared with the fruiting body and its extracts, which are entirely beta-glucan in nature.
Many Ganoderma species produce large amounts of oxidized lanostane triterpenes in a complex mixture. Ganoderma triterpenes are unique to the genus. Some G. lucidum triterpenes have been found to inhibit cancer cell line growth, although many of the major triterpenes are relatively weak inhibitors or inactive.[15-17] Analytical studies have examined the relative amounts of the different triterpenes in fruiting bodies, as well as in mycelial preparations.[18,19] The mammalian metabolism of the triterpenes singly, and in combination, has been studied with numerous sites of metabolism identified.
In vitro studies
Several G. lucidum-derived products have been studied in preclinical models and reported to produce anticancer effects. Both triterpenoids and polysaccharides cause cell growth arrest and cytotoxicity.[21-30] Studies of the cellular pathway by which G. lucidum triterpenoids produce cytotoxicity have generally implicated apoptosis pathways, both the intrinsic or mitochondrial pathway [21,23-25,27] and the extrinsic or death receptor pathway. Triterpenoids also inhibit adhesion and migration of malignant cells.[22,31,32] The lipid and protein components of G. lucidum have been less studied but also have demonstrated in vitro cytotoxicity.[33,34]
Other potential mechanisms of anticancer activity have been demonstrated, including reports of the induction of differentiation of neuroblastoma cells in vitro  and the inhibition of cellular secretion of factors associated with tumor-induced angiogenesis, such as vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta.
Ganoderenic acid B, a G. lucidum derived triterpene, has been shown to enhance the cytotoxicity of chemotherapeutic agents in a drug-resistant cell line of hepatocellular carcinoma by inhibiting the transport function of the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily transporters. This finding led the investigators to conclude that ganoderenic acid B may have the potential to be developed into a multidrug resistance reversal agent.
In vivo studies
Relatively few studies have explored the in vivo effects of G. lucidum in animal models, but those available have shown antitumor activity of triterpenoids in mice bearing Lewis lung carcinoma  and antitumor effects of polysaccharides in mice bearing S180 cells  and Ehrlich ascites cells.
There are no studies of G. lucidum with measured cancer outcomes. Building on the preclinical evidence that the polysaccharide fractions of G. lucidum enhance host immune function and have potential antitumor activity, investigators studied an over-the-counter product in patients with advanced stage lung cancer. Patients received Ganopoly, an aqueous polysaccharide fraction extracted from G. lucidum fruiting bodies. In an open-label trial, 36 patients with advanced lung cancer at a hospital in China, enrolled and 30 were accessible for immune function after 12 weeks. The patients were treated with chemotherapy or radiation therapy, and other complementary therapies. Ganopoly was administered as 1800 mg capsules 3 times daily before meals for 12 weeks. Treatment did not significantly alter the mean mitogenic reactivity to phytohemagglutinin; mean counts of lymphocyte subsets CD3, CD4, CD8, and CD56; mean plasma concentrations on interleukin-2, interleukin-6, or interferon-gamma; or natural killer cell activity (P > .05). The investigators noted that some patients did experience some significant changes in the parameters studied, but the group effect was null overall. The same group of investigators conducted a similar study of Ganopoly in 47 patients with advanced colorectal cancer and reported the exact same findings as seen in the lung cancer cohort.
Another mechanistic study in China investigated whether G. lucidum polysaccharides could counteract the immune suppression mediated by the plasma of patients with lung cancer. It is postulated that cancer cells release immunosuppressive mediators such as PGE2, TGF-beta, IL-10, and VEGF to inhibit the immune response and escape from immune surveillance. G. lucidum polysaccharides had been shown to counteract this immune suppression in an animal cell culture model; therefore, this experiment was undertaken to evaluate whether the effect could be duplicated in humans. Blood was obtained from 12 lung cancer patients. The G. lucidum polysaccharides were isolated from a boiling water extract of G. lucidum fruit bodies by ethanol precipitation. CD69 expression on mononuclear lymphocytes after phytohemagglutinin stimulation was inhibited markedly compared with controls (P = .05) after a 24-hour incubation with lung cancer patient plasma. G. lucidum polysaccharides at concentrations of 3.2 μg/mL and 12.8 µg/mL significantly antagonized this inhibition (P < .05 for both). Similar results were observed with additional assays leading the investigators to conclude that lung cancer patient plasma-induced suppression of lymphocyte activation by phytohemagglutinin may be fully or partially antagonized by G. lucidum polysaccharides, making them an attractive adjuvant in cancer treatment.
Japanese investigators studied a water-soluble extract from a cultured medium of G. lucidum mycelia (MAK) in patients with colorectal adenomas. After being diagnosed with colorectal adenomas on colonoscopy, 123 patients were enrolled in the MAK treatment group, and 102 no-treatment controls were randomly selected from the department’s patients. The treatment group was administered 1.5 g/d of MAK for 12 months. Both groups underwent repeat colonoscopy at 12 months. The change in the number of adenomas was +0.66 +/- 0.10 in the control group and -0.42 +/- 0.10 in the treated group (P < .01). The total size of adenomas increased by 1.73 +/- 0.28 mm in the control group and decreased by -1.40 +/- 0.64 mm in the MAK group (P < .01). These results suggest that MAK may suppress the development of premalignant colorectal adenomas.
- Raja HA, Baker TR, Little JG, et al.: DNA barcoding for identification of consumer-relevant mushrooms: A partial solution for product certification? Food Chem 214: 383-92, 2017. [PUBMED Abstract]
- Hennicke F, Cheikh-Ali Z, Liebisch T, et al.: Distinguishing commercially grown Ganoderma lucidum from Ganoderma lingzhi from Europe and East Asia on the basis of morphology, molecular phylogeny, and triterpenic acid profiles. Phytochemistry 127: 29-37, 2016. [PUBMED Abstract]
- Zhang X, Xu Z, Pei H, et al.: Intraspecific Variation and Phylogenetic Relationships Are Revealed by ITS1 Secondary Structure Analysis and Single-Nucleotide Polymorphism in Ganoderma lucidum. PLoS One 12 (1): e0169042, 2017. [PUBMED Abstract]
- Liao B, Chen X, Han J, et al.: Identification of commercial Ganoderma (Lingzhi) species by ITS2 sequences. Chin Med 10: 22, 2015. [PUBMED Abstract]
- Hong SG, Jung HS: Phylogenetic analysis of Ganoderma based on nearly complete mitochondrial small-subunit ribosomal DNA sequences. Mycologia 96 (4): 742-55, 2004 Jul-Aug. [PUBMED Abstract]
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Changes to This Summary (10/05/2020)
Added text to state that another Trametes species used primarily in China is Trametes robiniophila Murr, also known as Huaier.
Revised text to state that a monoclonal antibody that neutralizes Polysaccharide-K’s (PSK’s) antitumor effects has been used to validate the presence of PSK in implanted tumors.
Revised text to state that the nonselective protein kinase inhibitor hypothemycin and the adipocyte fat accumulation–inhibitory cyclic peptide ternatin have also been isolated from cultures of Trametes versicolor (cited Miller et al. as reference 10).
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PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Medicinal Mushrooms. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/mushrooms-pdq. Accessed <MM/DD/YYYY>. [PMID: 27929633]
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