The Role of Medicinal Mushrooms in Cancer Therapy

Martin PowellBSIO Meeting, London – 29/09/14

SHEN NONG BEN CAO 2nd Century AD

• Fu Ling (Poria cocos) • Yun Zhi (Coriolus versicolor) • Ling Zhi (Ganoderma lucidum -

Reishi)• Bai Mu Er (Tremella fuciformis -

Snow Fungus).

All classified as Superior Herbs, defined as having excellent therapeutic action, few or no side effects, may safely be taken for long periods and of which it is said that ‘prolonged use will lighten the body and confer longevity’!

• In a 15 year study of 174,505 inhabitants of the Nagano area of Japan, mushroom farmers were found to have a much lower rate of death from cancer than the general population (97.1/100,000 cf. 160.1/100,000).1

• An epidemiological study of 2,000 Chinese women, half with breast cancer and half without, found a reduction in risk of breast cancer in those women who regularly consumed mushrooms (10g/day fresh or 4g/day dried) and drank green tea (1.05g/day dried green tea leaves) with an increased reduction in women who did both. 2

• Two Korean studies comparing women with histologically confirmed breast cancer and an equal number of women without breast cancer also found a strong inverse correlation between mushroom consumption and breast cancer risk. 3

1. Zhang M, Huang J, Xie X, Holman CD. Dietary intakes of mushrooms and green tea combine to reduce the risk of breast cancer in Chinese women. Int J Cancer. 2009 Mar 15;124(6):1404-8.

2. Ikekawa T. Cancer Risk Reduction by Intake of Medicinal Mushrooms. Int J Med Mush. 2005;7(3):3473. Hong SA, Kim K, Nam SJ, Kong G, Kim MK. A case-control study on the dietary intake of mushrooms and breast cancer

risk among Korean women. Int J Cancer 2008;122(4):919-23

Mushroom-derived anti-cancer agents licensed in Japan

KRESTIN / PSK

(oral)

LENTINAN

(injection)

SIZOFRAN / SPG

(injection)

Trametes versicolor

(Coriolus) mycelium

Lentinula edodes

(Shiitake) fruiting

body

Schizophyllan commune

culture medium

May 1977 Dec 1985 Apr 1986

Digestive, lung and

breast cancer

Stomach cancer Cervical cancer

Stomach Cancer

Stage IV

Kaibara et al, 1976

Surgery w/MMC

+/- PSK w/chemo

66 PSK w/chemo doubled 2-

yr survival

Advanced Stomach

Cancer with

Metastases

Kodama et al, 1982

Surgery w/MMC

+/- PSK w/chemo

450 PSK w/chemo doubled 5-

yr survival

Stomach Cancer

Stage III – DOUBLE

BLIND

Kondo and Torisu, 1985

Surgery/no chemo +/-

PSK

144 PSK extended disease-

free period and enhanced

immunity

Advanced Stomach

Cancer with

Metastases

Maehara et al. 1990

Surgery + MMC + chemo

+/- PSK

255 PSK w/chemo extended

15-yr survival

Stomach Cancer I-

IV

Nakazato et al,1994

Surgery +chemo +/-PSK

253 PSK extended 5-yr

survival and disease-free

period

PSK CLINICAL TRIALS – STOMACH CANCER

Kidd P. The use of mushroom glucans and proteoglycans in cancer treatment. Alternative Medicine Review: A Journal of Clinical Therapeutic 2000; 5:4–27

Colorectal Cancer

DOUBLE BLIND

Kondo and Torisu, 1990

Surgery/no chemo +/-

PSK

110 PSK extended 8-yr

survival and disease-free

period

Oesophageal Ogoshi et al, 1995

Surgery + radio. +/-

chemo. +/- PSK

158 PSK extended 5-yr post

surgery+RT+CT and

normalised serum factors

Lung (NSCLC)

Stages I-III

Hayakawa et al, 1993

Radiotherapy +/- PSK

185 PSK extended 5-yr

survival 2-4x all stages.

<5cm >70yr max benefit

Breast, ER+/- Stage

II, post-surgery

Toi et al. 1992

MMC +/- Tamoxifen +/-

Ftorafur +/- PSK

914 PSK extended survival in

ER-neg, non-metastasized

Breast Stages I, II Iino et al, 1995

FEMP chemotherapy +

Levamisole or PSK

227 PSK trend to extend 10-yr

survival + disease-free

period. HLA B40+ 100%

PSK CLINICAL TRIALS – OTHER CANCERS

• In a systematic review and meta-analysis aggregating and analyzing the efficacy of Coriolus exracts on survival of cancer patients from 13 randomized, placebo-controlled clinical trials, Coriolus was found to result in a significant survival advantage compared with standard conventional anti-cancer treatment alone.

• Of patients randomized to Coriolus, there was a 9% absolute reduction in 5-year mortality, resulting in one additional patient alive for every 11 patients treated. In patients with breast cancer, gastric cancer, or colorectal cancer treated with chemotherapy, the effects of the combination of Coriolus preparation on the overall 5-year survival rate was more evident, but not in esophageal cancer and nasophayngeal carcinoma.

• Subgroup analysis could not conclude which type of anti-cancer treatment may maximize the benefit from Coriolus.

Eliza WL, Fai CK, Chung LP. Efficacy of Yun Zhi (Coriolus versicolor) on survival

in cancer patients: systematic review and meta-analysis. Recent Pat Inflamm

Allergy Drug Discov. 2012 Jan;6(1):78-87.

MD Anderson Cancer Centre’s Detailed Scientific Review of Coriolus

• ‘Coriolus is a promising candidate for chemoprevention due to the multiple effects on the malignant process, limited side effects and safety of daily oral doses for extended periods of time.’

• PSK and PSP seem to work at multiple steps of the malignant process by inhibiting adhesion, invasion, motility, and metastatic growth of tumor cells in animal models of cancer.

• Adhesion and invasion are inhibited by suppression of cell matrix-degrading enzyme production by malignant cells.

• Motility of malignant cells and subsequent attachment to blood vessels are inhibited by suppression of tumor-cell induced platelet aggregation and anti-angiogenic factors.

http://www.coriolusversicolor.us/wp-content/uploads/2010/09/coriolus-versicolor-medical-trials-4001.pdf

• Immune responsiveness of the host does not appear to be affected by PSK under normal conditions, but immune systems depressed by tumor-burden or chemotherapy, have reportedly been restored to normal levels by PSK in animal studies.

• Immune restoration has included antibody and cytokine production and improvement of impaired antitumor activity of natural killer cells, T cells, macrophages and peripheral blood lymphocytes in vivo and in vitro.

• PSK has also been demonstrated to inhibit the decline of immunocompetence during the perioperative period and inhibit the growth of residual tumors following cryoablation.

• PSP has also been shown to reverse tumor-induced immunodeficienciesin sarcoma-bearing mice by increasing immunoglobulin G and C3 complement levels. It has also been associated with increases in white blood cell count, CD4, CD8, B-lymphocytes, and neutrophils, along with a higher survival rate of tumor bearing mice.

• PSK has been associated with side effects of gastrointestinal upset and darkening of the fingernails, but these effects have been limited and general safety has been demonstrated with daily oral doses for extended periods of time. It does not seem to interact with hepatic drug-metabolizing enzymes involved in the chemical processing of most chemotherapy agents, and no genetic damage has been detected by the Ames test.

• At doses that produced necrotic changes in tumor cells, PSP produced no lesions in the vital organs of tumor-bearing mice after treatment for two months. It has not been associated with teratogenic effects in mice or rats.

• 1994 Gastric cancer trial by the Nakazato and Koike of the Study Group for Immuno-chemotherapy reported in the Lancet (1994;343:1122-1126) concluded that no toxic effects could be observed from PSK “even after meticulous review of all the patient records”.

Toxicology of PSK

Meta-analysis of 5 clinical trials with a total of 650 participants showed that the addition of lentinan at 2mg/week to standard chemotherapy offers a significant advantage over chemotherapy alone in terms of survival for patients with advanced gastric cancer, with patients with lymph node metastasis having slightly better results than those with non-lymph node metastasis . 1

1. Individual patient based meta-analysis of lentinan for unresectable/recurrent gastric cancer. Oba K, Kobayashi

M, Matsui T, Kodera Y, Sakamoto J. Anticancer Res. 2009 Jul;29(7):2739-45.

LentinanFrom Lentinula edodes

(Shiitake)

• Additional trials confirm increased survival, reduced side effects from chemotherapy and improved quality of life in patients with colorectal, hepatocellular, breast cancer and metastatic prostate cancer. In a trial with 69 patients with metastatic prostate cancer the 50% survival length of treated and control patients was 48 and 35 months, respectively while the the five-year survival rate of treated patients was 43% against 29% in the control group1,2.

• Although usually delivered by injection, Lentinan is also orally bioavailable although the clinical dosage is likely to be significantly higher 3,4.

1. [Effects of lentinan in advanced or recurrent cases of gastric, colorectal, and breast cancer]. Taguchi T.

Gan To Kagaku Ryoho. 1983 Feb;10(2 Pt 2):387-93. [Article in Japanese]

2. [Effect of lentinan for advanced prostate carcinoma]. Tari K, Satake I, Nakagomi K, Ozawa K, Oowada F,

Higashi Y, Negishi T, Yamada T, Saito H, Yoshida K. Hinyokika Kiyo. 1994 Feb;40(2):119-23.

3. Inhibition of human colon carcinoma development by lentinan from shiitake mushrooms (Lentinus

edodes). Ng ML, Yap AT. J Altern Complement Med. 2002 Oct;8(5):581-9.

4. The Medicinal Benefits of Lentinan (β-1, 3-D glucan) from Lentinus edodes (Berk.) Singer (Shiitake

Mushroom) Through Oral Administration. Yap AT, Ng MH. Int J Med Mushr. v7.i12.170

In a non-randomised study of 165 patients with stage III-IV cancer given Maitake D-fraction with Maitake fruiting body tumour regression and/or significant symptomatic improvement was seen in 66% of lung cancer patients, 54% of liver cancer patients, 56% of pancreatic cancer patients and 74% of breast cancer patients1.

1. Anti tumor activity of orally administered d-fraction from Maitake (Grifola frondosa). Nanba H. J

Naturopathic Medicine. 1993 1:10-15

Grifola frondosaMaitakeHen of the Woods

D-fraction / MD-fraction

• In a separate study a combination of MD-fraction and whole Maitake fruiting body powder was reported to produce similar improvements: 58.3% of liver cancer patients, 68.8% of breast cancer patients and 62.5% of lung cancer patients1.

• In vivo studies also showed synergy between D-fraction and chemotherapy (mitomycin C) as well as significant alleviation of side effects from chemotherapy, including loss of appetite, vomiting, nausea, hair loss and leukopenia2.

1. Can Maitake MD-Fraction Aid Cancer Patients? Kodama N, Komuta K, Nanba H. Alt Med Rev. v.7,3. 2002

2. Maitake extracts and their therapeutic potential - A Review. Mayell M. Alt Med Rev, v.6.1. 2001

• A. blazei polysaccharide extracts show strong in-vitro and in-vivo activity against a range of cancer cell lines, including: lung and ovarian cancer1.

• Clinical studies are limited although Mizuno reports positive clinical results in a number of mainly breast cancer patients at unspecified dosage while Ahn reports increased NK-cell activity and reduced chemotherapy related side effects from A. blazei polysaccharide extract2.

• A 2008 study confirms increases in NK cell activity with A. blazei polysaccharide extract a dose of 3g/day3.

1. Antitumor beta-glucan from the cultured fruit body of Agaricus blazei. N. Ohno, M. Furukawa and N. Miura. Biol. Pharm. Bull. 24 (2001),

pp. 820–828.

2. Medicinal properties and clinical effects of culinary-medicinal mushroom Agaricus blazei Murrill (Agaricomycetideae) (Review). T.

Mizuno. Int. J. Med. Mushr. 4 (2002), pp. 299–312.

3. Immunomodulating Activity of Agaricus brasiliensis KA21 in Mice and in Human Volunteers. Liu Y, Fukuwatari Y, Okumura K, Takeda K,

Ishibashi KI, Furukawa M, Ohno N, Mori K, Gao M, Motoi M. Evid Based Complement Alternat Med. 2008 Jun;5(2):205-219.

Agaricus subrufescens

(Agaricus blazei / brasiliensis)

Almond Mushroom

1-3, 1-6-Beta Glucan

Lentinan - a polysaccharide isolated from Shiitake

and licensed in Japan as a pharmaceutical drug.

Heteropolysaccharides – as well as Glucose mushroom polysaccharides typically contain other sugars, such as Mannose, Galactose, Xylose, Fucose, e.g.:

• Xylogalactoglucan – Inonotus obliquus (Chaga)

• Glucomannan – Agaricus blazei

• Galactoglucomannan – Lentinus edodes (Shiitake)

• Mannogalactofucan – Grifola frondosa (Maitake)

• Galactoxyloglucan – Hericium erinaceous (Lion’s Mane)

• Glucoronoxylomannans – Tremella fuciformis (Snow Fungus)

• -

Although most research has focussed on β Glucans, especially β-1,3 and β-1,4 linked, α-1,4 and α-1,6 glucans have also shown anti-tumour activity

It also appears that the most active polysaccharide fractions have bound protein components (proteoglycans).

Medicinal mushrooms as a source of antitumor and immunomodulating polysaccharides. S.P.

Wasser. Appl Microbiol Biotechnol (2002) 60:258-274

PSK (Krestin) and PSP from Trametes versicolor

• PSK is a a purified hot-water extract consisting of protein-bound polysaccharide molecules with an average molecular weight of 94kDa.

• Protein component ranges from 25-38%.

• The main constituent monosaccharide is glucose wıth small amounts of other sugar residues, such as mannose, fucose, xylose and galactose. The main chain consists ofbeta 1-4 linked units with side chains of beta 1-3 as well as beta 1-6 linked glucose residues.

• PSP is similar to PSK but differs in the presence of rhamnose and arabinose.

Renn L, Prera C, Hemar Y. Antıtumor actıvıty of mushroom polysaccharıdes:a revıew. Food Funct. 2012;3:1118-1130.

Immune changes induced by mushroom polysaccharide-based supplementation include:

• Increased NK cell activation

• Increased macrophage activation

• Increased cytotoxic T-cell activation

• Increased IFN-γ, IL-2 and TNF-β production

• Reduced IL-4 production

• Inhibition of prostaglandin synthesis

TH1 TH2

Cellular Immunity / Cytotoxic Humoral (Antibody mediated) Immunity / Pro-inflammatory

Interferon-γ and TNF-β IL-4, IL-5, IL-6, IL-13

High NK cell activity and classical (antimicrobial) macrophage activation

Low NK cell activity and alternative (proliferative and collagen producing) macrophage activation

Infectious diseases Chronic inflammatory conditions

TH1 TH2

Presence of older siblings Stress / Cortisol

Early exposure to day care Chemical and heavy metal exposure

Infectious diseases in childhood Multiple vaccinations

Factors promoting the development of Th1 and Th2 phenotypes

Mikael Häggström - Rang, H. P. (2003) Pharmacology, Edinburgh: Churchill Livingstone Page 223

Consequences of a TH1 - TH2 Shift

• Lowered resistance to viral and other pathogens.

• Increases in fatigue and incidence of depression.

• Increases incidence of allergic and auto-immune conditions such as asthma and SLE.

• Persistent humoral immune responses exacerbate recruitment and activation of innate immune cells in neoplastic microenvironments where they regulate tissue remodelling, pro-angiogenic and pro-survival pathways that together potentiate cancer development.1

1. Tan TT, Coussens LM. Humoral immunity, inflammation and cancer. Curr Opin Immunol. 2007 Apr;19(2):209-16

• Commonly expressed in macrophages, neutrophil lineages, dendritic cells and some T-cells but not NK-cells.

• Considered the most important receptor for the activation of the innate immune response in macrophages.

• Binds specifically to β-(1→3)-glucans but only those consisting of at least 10 monomers

• Binding activates phagocytosis, ROS production and induction of TNF-α, IL-2, IL-10, IL-12

Medicinal Importance of fungal β- (1→3), (1→6)-glucans. Jiezhong Chen, Robert Seviour. Mycological Research

III (2007). 635-652

Dectin-1

• Expressed mainly on Neutrophils, Monocytes and NK Cells.

• Two binding sites exist on the CD11b domain. One for β-glucans and the other for iC3b (cleaved component 3 fragment of serum complement system).

• Binding of β-glucans to CR3 increases adhesion to microbial cells and activates the iC3b pathway causing tumour cytotoxicity.

Medicinal Importance of fungal β- (1→3), (1→6)-glucans. Jiezhong Chen, Robert Seviour. Mycological

Research III (2007). 635-652

CR3

The effects of β-glucan on human immune and cancer cells. Godfrey Chi-Fung Chan, Wing Keung Chan

and Daniel Man-Yuen Sze. Journal of Hematology & Oncology 2009, 2:25

• Lentinan extended survival and reduced the incidence of adverse effects in inoperable or recurrent gastric cancer in conjunction with tegafur as well as S-1-based chemotherapy (tegafur, gimeracil, oteracil).

• Five-year disease free survival in colorectal cancer cases was significantly higher with PSK and oral Tegafur/Uracil (UFT) than with UFT alone (73% vs. 58.8%) and increased five-year disease-free period (70.7% vs. 59.4%) and survival (73.0% vs. 60.0%) in gastric cancer when given together with mitomycin and fluoracil.

Mushrooms and Chemotherapy

• Agaricus subrufescens polysaccharide extract reduced chemotherapy related side effects (appetite, alopecia, emotional stability, and general weakness) in 100 cervical, ovarian, and endometrial cancer patients treated either with carboplatin plus VP16 (etoposide) or with carboplatin plus taxol.

• Grifola frondosa polysaccharide fractions potentiated the action of carmustine and increased efficacy when given in combination with chemotherapy across a range of cancers, as well as reducing cisplatin-induced nephrotoxicity.

In addition to supporting the immune system and ameliorating chemotherapy-induced immune suppression there is some evidence that mushroom polysaccharide extracts contribute to the efficacy of the chemotherapeutic drugs themselves through enhanced production of reactive oxygen species (ROS):

• Liu et al reported an increase in ROS and reactive nitrogen intermediates in peritoneal macrophages of mice given PSP.

• An extract of A. subrufescens was shown to induce apoptosis through an ROS-dependent pathway.

• Grifron-D, a polysaccharide extract from G. frondosa, has been shown to have a direct cytotoxic effect on cancer cells through oxidative membrane damage leading to apoptosis.

• Reduction in radiation-induced leukopaenia - in a trial with 136 patients undergoing radiotherapy, oral consumption of T. fuciformis polysaccharide extract (3g/day) resulted in a 13.2% reduction inWBC compared to a 35.2% reduction in the control group and T.versicolor mycelial biomass (6g/day) prevented decreases in red and white blood cells in lung cancer patients undergoing radiotherapy.

• Enhanced treatment efficacy - oral administration of T.versicolor extract PSP with radiotherapy significantly increased the percentage of apoptotic cells at 24hr compared to radiation alone and reduced radiotherapy induced reduction in white blood cell count.

Mushrooms and Radiotherapy

Recent research indicates that mushroom polysaccharides have a prebiotic effect on the gut microbiome with increases in Bifidobacterium and Lactobacillus species and decreases in Clostridium, Staphylococcus and Enterococcusspecies, together with increased concentration of organic acids (lactate and short-chain fatty acids), decreased pH and increased β-galactosidase and β-glucosidase activity and it has been suggested that this effect may also contribute to their diverse health benefits1,2.

1. Trametes versicolor extract modifies human fecal microbiota composition in vitro. Yu ZT, Liu B, Mukherjee P, Newburg DS. Plant Foods Hum Nutr. 2013 Jun;68(2):107-12.

2. Effects of polysaccharopeptide from Trametes Versicolor and amoxicillin on the gut microbiome of healthy volunteers: A randomized clinical trial. Pallav K. et al. Gut Microbes. 2014 Jul 9;5(4).

Mushrooms’ Prebiotic Activity

A 1 year controlled trial using Coriolus versicolor mycelial biomass in 43 LSIL HPV patients reported results including:

• Cytology returned to normal in 72.5% of patients receiving Coriolus supplementation (3g/day) compared to 47.5% in the control group.

• 90% of patients who received supplementation became –ve for High Risk HPV strains compared to 8.5% in the control group.

CORIOLUS SUPPLEMENTATION FOR LSIL

Coriolus versicolor supplementation in HPV patients. Couto S. 20th European Congress of Obstetrics and Gynaecology, 2008.

Immunologically active polysaccharides

Secondary metabolites

ACTIVE COMPOUNDS FROM MEDICINAL

MUSHROOMS

Differ from species to species

Found in all mushrooms

Fruiting Body - mg/kg Mycelium - mg/kg

Porcini 131

Reishi 68 908

Oyster (Korea) 60

Oyster (Taiwan) 147

Golden Oyster 930

Buna-Shimeji 628

Shiitake 316

Agaricus subrufescens 184

Lovastatin

Lin SY, Chen YK, Yu HT, Barseghyan GS, Asatiani MD, Wasser SP, Mau JL. Comparative study of contents of several bioactive components in fruiting bodies and mycelia of culinary-medicinal mushrooms. Int J Med Mushrooms. 2013;15(3):315-23.

Originally isolated from Penicillium brevicompactum as an anti-fungal agent (called Compactin), as well as from Penicillium citrinum and is widespread in mushrooms and other fungi.

• Mushrooms produce a wide range of anti-fungal compounds to help them compete with other fungi. 1-3

• Mushrooms help facilitate the immune system’s response to respond candida. 4-6

• Mushrooms do not contain sugars or starches that could stimulate the growth of candida.

1. An examination of antibacterial and antifungal properties of constituents of Shiitake (Lentinula edodes) and oyster (Pleurotus ostreatus)

mushrooms. Hearst R, Nelson D, McCollum G, Millar BC, Maeda Y, Goldsmith CE, Rooney PJ, Loughrey A, Rao JR, Moore JE. Complement

Ther Clin Pract. 2009 Feb;15(1):5-7.

2. Antimicrobial properties of shiitake mushrooms (Lentinula edodes). Rao JR, Smyth TJ, Millar BC, Moore JE. Int J Antimicrob Agents. 2009

Jun;33(6):591-2.

3. Antimicrobial and antineoplasic activity of Pleurotus ostreatus. Wolff ER, Wisbeck E, Silveira ML, Gern RM, Pinho MS, Furlan SA. Appl

Biochem Biotechnol. 2008 Dec;151(2-3):402-12.

4. Protective effects of a protein-bound polysaccharide, PSK, on Candida albicans infection in mice via tumor necrosis factor-alpha induction.

Ohmura Y, Matsunaga K, Motokawa I, Sakurai K, Ando T. Int Immunopharmacol. 2001 Sep;1(9-10):1797-811.

5. Paccola E, Maki C, Nobrega G, Paccola-Meirelles L. Antagonistic Effect of Edible Mushroom Extract on Candida Albicans Growth. Braz. J. of

Microbiol. (2001) 32:176-178

6. Polysaccharide-rich fraction of Agaricus brasiliensis enhances the candidacidal activity of murine macrophages. Martins PR, Gameiro MC,

Castoldi L, Romagnoli GG, Lopes FC, Pinto AV, Loyola W, Kaneno R. Mem Inst Oswaldo Cruz. 2008 May;103(3):244-50.

Mushrooms’ Anti-Candida Activity

Ling Zhi (Reishi)Ganoderma lucidum

Ling Zhi – Spirit Mushroom

Mushroom of Immortality

Mannantake – 10,000 Year

Mushroom

Reishi

• Anti-cancer

• Anti-inflammatory

• Anti-histamine

• Anti-allergic

• Sedative

• Anti-hypertensive

• Antioxidant

• Hepatoprotective

• Anti-cholesterol

• 5 randomised controlled trials met inclusion criteria.

• The meta-analysis results showed that patients who had been given G. lucidum alongside chemo/radiotherapy were 1.27 times more likely to respond positively to chemo/radiotherapy compared to those without.

• G. lucidum treatment alone did not demonstrate the same regression rate as that seen in combined therapy.

• Four studies showed that patients in the reishi group had relatively improved quality of life in comparison to controls. Only one of the studies recorded minimal side effects, including nausea and insomnia.

• The results for host immune function indicators suggested that G. lucidum simultaneously increases the percentage of CD3, CD4 and CD8.

Jin X, Ruiz Bequerie J, Sze DM, Chan GC. Ganoderma lucidum (Reishi mushroom) for cancer treatment.

Cochrane Database Syst Rev. 2012 Jun 13;6:CD007731

Cochrane Database Systematic Review of the Use of

Ganoderma Lucidum for Cancer Treatment

Ganoderic and Lucidenic Acids

• Sedative effect on CNS

• 9 lucidenic acids and 4 ganoderic acids showed strong anti-

inflammatory activity

• Inhibit histamine release (Ganoderic Acids A,B,C and D, also

Oleic Acid and Cycooctasulphur)

• Anti-hepatotoxic (R,S and Ganodosterone)

• Anti-hypertensive (ACE inhibition - B,D,F,H,K,S,Y)

• Anti-viral - 11 lucidenic acids and 5 ganoderic acids showed

strong inhibition of EBV. Ganoderma triterpenes also inhibit

HIV-1 protease activity and viral binding and showed potent

inhibitory activity against herpes simplex virus

• Anti-cancer

Anti-tumour Activity of Ganoderic and Lucidenic Acids

• Suppression of cancer growth and angiogenesis through modulation of AP-1 and NF-kB signalling

• Induction of apoptosis via a mitochondria-mediated pathway

• Inhibition of cancer cell invasiveness

• Inhibition of aromatase activity

• Suppression of steroid 5α-reductase, which converts testosterone to dihydrotestosterone (DHT) and has been shown to play an important role in the development of prostate cancer and benign prostatic hyperplasia (BPH)

• Enhanced chemosensitivity to cisplatin through inhibition of the JAK-STAT3 signalling pathway

Anti-cancer properties of triterpenoids isolated from Ganoderma lucidum - a review. Wu GS et al. Expert Opin InvestigDrugs. 2013 Aug;22(8):981-92.

Spore Powder of Ganoderma lucidum Improves Cancer-Related Fatigue in Breast Cancer Patients Undergoing Endocrine Therapy: A Pilot Clinical Trial

• 48 breast cancer patients with cancer-related fatigue undergoing endocrine therapy with treatment group given 3g/day shell-broken spore powder.

• Significant improvements in physical well-being and fatigue.

• Reductions in anxiety and depression and improved quality of life.

• Immune markers of CRF were significantly lower.

1. Spore Powder of Ganoderma lucidum Improves Cancer-Related Fatigue in Breast Cancer Patients Undergoing Endocrine Therapy: A Pilot Clinical Trial. Zhao H, Zhang Q, Zhao L, Huang X, Wang J, Kang X. Evid Based Complement Alt Med. Epub 2011 Dec 10.

Inonotus obliquusChaga – Bai Hua Rong

Widely used as a folk medicine in Russia

and eastern europe to treat cancer and

support the immune system. Credited

with curing Solzhenitzen of cancer.

Contains high levels of betulinic acid

(also one of the key components in

mistletoe) derived from the bark of host

birch trees, with actions including:

• Anti-retroviral• Anti-malarial • Anti-inflammatory • Anti-cancer

Betulinic Acid and Cancer

• Induces mitochondrial apoptosis in different cancer cell lines and inhibits the enzyme topoisomerase, which is essential for the unwinding and winding of the DNA strands in cell replication.

• In-vitro studies on betulinic acid have shown it to be highly effective against a wide variety of cancer cells: human melanoma, neuroectodermal (neuroblastoma, medulloblastoma, Ewing's sarcoma) and malignant brain tumors, ovarian carcinoma, human leukemia HL-60 cells and malignant head and neck squamous cell carcinomas, including those derived from therapy-resistant and refractory tumors.

Mullauer FB, Kessler JH, Medema JP. Betulinic acid, a natural compound with potent anticancer effects. Anticancer Drugs. 2010 Mar;21(3):215-27.

• Betulinic acid's action against brain tumor cells is particularly interesting and it is noteworthy that in one study it exerted cytotoxic activity against primary tumor cells cultured from patients in 4 of 4 medulloblastoma-tumor samples tested and in 20 of 24 glioblastoma-tumor samples.

• It also shows great promise in combination with radiotherapy, exhibiting a strictly additive mode of growth inhibition in combination with radiation in human melanoma cells in one study and acting as a radiosensitizer in head and neck squamous cell cancers in another.

Mullauer FB, Kessler JH, Medema JP. Betulinic acid, a natural compound with potent anticancer effects. Anticancer Drugs. 2010 Mar;21(3):215-27.

CordycepsOphiocordyceps sinensis

/ Cordyceps militaris

• Anti-fatigue – Cordyceps has been shown to increase endurance, efficiency of oxygen utilization and cellular ATP levels. In a trial with 50 asthma patients 81.3% showed improvement with an average of 5 days using Cordyceps compared to 61.1% taking antihistamines with an average of 9 days for symptoms to subside.

• Hepato-protective – inhibits hepatic fibrogenesis derived from chronic liver injury, retards the development of cirrhosis, reduces liver enzyme levels and significantly improves liver function.

• Anti-cholesterol – decreases plasma cholesterol in rats fed a cholesterol enriched diet and increases ratio of HDL to LDL.

• Anti-stress – equivalent to ginseng. Counteracted inhibition of weight gain, increase in adrenal gland weight, increase in glucocorticoid receptors in the liver, spleen and thymus and increased peroxidation in the liver and heart.

• Immuno-modulatory and anti-cancer – activates macrophages, stimulates bone marrow cell proliferation through activation of Peyer’s patch cells.

Nucleoside Analogues

Adenosine 3-deoxyadenosine 2,3-dideoxyadenosine

Cordycepin

Forerunner of

Didanosine (Videx)

Cordycepin

• Inhibits cancer cell replication1

• Inhibits invasiveness of cancer cells2

• Induces apoptosis of multiple cell lines, including:

• Leukaemia

• Multiple myeloma

• Prostate cancer

• Neuroblastoma

• Oral Cancer

• Anti-inflammatory

1. Lee HJ, Burger P, Vogel M, Friese K, Brüning A. The nucleoside antagonist cordycepin causes DNA double strand breaks in breast cancer cells. Invest New Drugs. 2012 Oct;30(5):1917-25

2. Jeong JW, Jin CY, Park C, Han MH, Kim GY, Moon SK, Kim CG, Jeong YK, Kim WJ, Lee JD, Choi YH. Inhibition of migration and invasion of LNCaP human prostate carcinoma cells by cordycepinthrough inactivation of Akt. Int J Oncol. 2012 May;40(5):1697-704.

Current Issues

• Lack of standardisation

• Different formats:

• Fruiting body

• Mycelium

• Hot-water extracts (polysaccharide-rich)

• Ethanolic extracts (triterpene-rich)

• Mycelial biomass (rich in anti-microbial secondary metabolites and substrate-breakdown products such as arabinoxylans but low in beta-glucans and related polysaccharides)

• Lack of comparative research

• Single mushrooms vs. combinations

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