Immune Modulation From Five Major Mushrooms: Application to Integrative Oncology

Abstract

This review discusses the immunological roles of 5 major mushrooms in oncology: Agaricus blazei, Cordyceps sinensis, Grifola frondosa, Ganoderma lucidum, and Trametes versicolor. These mushrooms were selected based on the body of research performed on mushroom immunology in an oncology model. First, this article focuses on how mushrooms modify cytokines within specific cancer models and on how those cytokines affect the disease process. Second, this article examines the direct effect of mushrooms on cancer. Finally, this article presents an analysis of how mushrooms interact with chemotherapeutic agents, including their effects on its efficacy and on the myelosuppression that results from it. For these 5 mushrooms, an abundance of in vitro evidence exists that elucidates the anticancer immunological mechanisms. Preliminary research in humans is also available and is promising for treatment.

Medicinal mushrooms have been proposed as a novel therapy that may improve cancer treatment and patients’ survival. They have been used medicinally since at least 3000 bce. Mushrooms are reported to have antimicrobial, anti-inflammatory, cardiovascular-protective, antidiabetic, hepatoprotective, and anticancer properties. It is well-established that mushrooms are adept at immune modulation and affect hematopoietic stem cells, lymphocytes, macrophages, T cells, dendritic cells (DCs), and natural killer (NK) cells.1 Extensive research over the last 40 years has demonstrated that mushrooms have potent antineoplastic properties that slow growth of tumors, regulate tumor genes, decrease tumoral angioneogenesis, and increase malignant-cell phagocytosis. Additionally, evidence suggests that medicinal mushrooms may safely boost chemotherapeutic efficacy and simultaneously protect against bone marrow suppression.

Mushrooms represent a unique branch of botanical medicine and are classified in the kingdom of Fungi. They reproduce as spores. The fungal body can be a single cell or a structure called a hypha or mycelial threads. The fruiting body grows off the hyphae and produces spores for reproduction (Figure 1). The common and scientific names of the mushrooms discussed in this article are found in Table 1. The 5 mushrooms explored in this paper have many active constituents including, but not limited to, polysaccharides, polysaccharide peptides, proteins, terpenoids, and nucleotides (Table 1). Many of the compounds studied have yet to be named and are often referred to by gel chromatography fraction when they are studied. The most common medicinally active ingredient among mushrooms is β-glucan.

Figure 1.

Mushroom Anatomy

Table 1.

Scientific and Common Names of Mushrooms and Their Major Constituents

Scientific Name	Common Name	Specific Constituent	Type of Constituent
Agaricus blazei	Agaricus	β-d-glucan	Polysaccharide
Ganoderma lucidum	Reishi, lingzhi	Ganoderic acid	Protein
		Danoderiol	Protein
		Danderenic acid	Protein
		Lucidenic acid	Protein
		GLPS	Polysaccharide
Cordyceps sinesis	Cordyceps, caterpillar mushroom	Adenosine	Nucleotide
		Cordycepin	Nucleotide
Trametes versicolor (formerly Coriolus versicolor)	Turkey tail	PSP	Polysaccharide peptide
		PSK	Polysaccharide peptide
Grifolia frondosa	Maitake	Grifolan	Polysaccharide
		D-fraction
		MD-fraction	Polysaccharide

Abbreviations: GLPS = Ganoderma lucidum polysaccharide; PSP = polysaccharide peptide; PSK = polysaccharide K.

Cancer Immunology

One of the myriad effects of mushrooms occurs through their ability to stimulate cytokine production. Cytokines are small, soluble proteins that act as intracellular mediators in an immune response. In the effort to understand cytokine responses and the interrelationships between cytokines, one approach has been to characterize a certain set of cytokines for responses to different situations. The cytokines involved in different types of responses are defined as cytokine patterns. Patterns of importance in cancer research include T_H1, T_H2, T_H3/T regulatory (Treg) cells, and the proinflammatory pathways. Each of these defined patterns can have a different physiological effect in a cancer patient (Table 2). Cytokines are cross-regulatory, and the expression of one pattern of cytokines can modulate other cytokine patterns. To evaluate the role of cytokines in disease, it is necessary to evaluate several cytokines from each pathway because the overall pattern may have a larger impact on the body than any individual cytokine.

Table 2.

Basic Cytokine Patterns

Pattern	Cytokines	Pattern Effect
TH1	IFN-γ, IL-12, TNF-α	Stimulates immune response to cancer
TH2	IL-4, IL-5, IL-13	Decreases TH1
TH3/Treg	TGF-β	Modulates TH1
Proinflammatory	IL-1, IL-6, IL-8, TNF-α	Causes inflammation

The cytokine pattern associated with a beneficial immune response to cancer is T_H1. The dominant T_H1 cytokine is IFN-γ, which is responsible for stimulating the cellular immune response. Cellular immunity is important in an antitumor response since NK and CD8+ T cells, as well as tumoricidal macrophages, can destroy tumor cells. In addition, a number of cellular functions, such as presentation of tumor-specific antigens and production of tumoricidal cytokines, are increased by IFN-γ. Thus, therapies, including use of mushrooms that increase IFN-γ and drive a T_H1 response, are beneficial for cancer patients.2

In contrast to a T_H1 response, a T_H2 response is not typically associated with an immune response to cancer. T_H2 responses are associated with allergies and asthma and involve the cytokines IL-4, IL-5, IL-13, and sometimes IL-10. Most important, IL-4 and IFN-γ cross-regulate each other. IFN-γ decreases production of IL-4, and IL-4 decreases production of IFN-γ. Thus, a T_H2 response can be detrimental to cancer patients because it decreases IFN-γ and decreases the cellular immune response to cancer.

Regulation of the T-cell response is accomplished by Treg cells, also called T_H3 or Treg cells. While many categories of Treg cells exist, most Tregs produce TGF-β (transforming growth factor β). This cytokine was discovered through its ability to increase the growth of tumor cells, mediated by decreasing the T_H1 response. TGF-β can also decrease T_H2 responses. Because it can decrease both T_H1 and T_H2, TGF-β is most commonly associated with tolerance and is found in high levels in the intestine and lungs, where large doses of innocuous antigens are frequently introduced. While it is beneficial to have a Treg response to self-antigens, Treg responses do not lead to cancer clearance.2

When associated with cancer, proinflammatory cytokines can contribute to inflammatory symptoms. These cytokines are released early in the immune response to infectious agents and are responsible for driving fever and stimulating the innate immune system. Many symptoms related to sickness—malaise, anxiety, and hostility, which are observed during infection are a result of these cytokines.3–10 For example, radiotherapy increases IL-1, IL-6, and TNF-α.11,12 A recent quantitative review of 1037 patients with cancer-related fatigue that partially resulted from radiotherapy demonstrated that IL-6 and IL-1RA were associated with fatigue; however, IL-1β and TNF-α were not linked to fatigue.13

In summary, when considering immunomodulatory effects of mushrooms, those that stimulate T_H1 responses may be beneficial in cancer treatment, as are those that decrease T_H2 and Treg responses. Mushrooms that decrease inflammation may have the added benefit of decreasing fatigue, anxiety, and other symptoms by decreasing inflammatory cytokines.

Immunomodulatory Effects of Mushrooms

Many studies have been conducted to elucidate the antitumor mechanisms of mushrooms. Rather than providing a summarization for each study in the text, this article provides Table 3, which summarizes cytokine modulation and the resulting pattern produced from Agaricus, maitake, reishi, Cordyceps, and turkey tail mushrooms. By the way they list each study, Table 3 and subsequent tables are organized such that human studies and in vivo studies are prioritized over in vitro and/or animal studies. Overall, the studies show a trend that indicates that each of these mushroom species increases T_H1 cytokine production in both in vitro and in vivo models. At this stage of the immunological research, a notable lack of randomized, placebo-controlled trials is evident. Another important difficulty with the data lies in the delivery methods and types of mushroom extract used. Animal studies often, although not exclusively, use an intraperitoneal (IP) injection of the purified mushroom extract. The pharmacodynamics of IP injection versus oral ingestion of mushrooms is not well researched and, thus, it is difficult to translate dosage and form into human studies.

Table 3.

Cytokine Modulation

Mushroom	In Vivo/Vitro/Model	Cytokine	Pattern	Dose/Preparation	Reference
Agaricus	In vivo, mouse cancer	IFN-γ	TH1	350 mg PO QD; hot water extract	Takimoto et al, 200815
Agaricus	In vivo, mouse leukemia	IFN-γ IL-6 IL-1β IL-4	TH1 PI	3 or 6 mg/kg PO × 3 wk; hot water extract	Lin, Fan, and Tang, 201216
Reishi	In vivo, advanced human lung cancer, prospective nonplacebo controlled trial with 36 participants	IL-2 56% IL-6 56% IFN-γ 56% IL-1 56.7% TNF-α 66.6%	TH1 PI	5.4 g/d PO; Ganopoly × 12 wk; hot water extraction, then 75% ethanol extraction, then purified by gel filtration	Gao et al, 200517
Reishi	In vivo, human late-stage cancer, prospective nonplacebo controlled trial with 34 participants	IL-2 IL-6 IFN-γ IL-1 TNF-α	TH1 PI	1800 mg Ganopoly PO TID × 3 mo; hot water extraction, then 75% ethanol extraction, then purified by gel filtration	Gao et al, 200318
Reishi	In vivo, mouse CT26 cancer	NF-κB TNF-α IL-1β	TH1 PI	50, 100, 200 mg/kg IP; standardized PSG-1 polysaccharide, compared to 5-fluorouracil or normal saline	Zhang et al, 201319
Reishi	In vivo, mouse lung cancer	IL-2 IFN-γ NF-κB	TH1	28 mg/kg IP; ganoderic acid-Me purified from Ganoderma lucidum	Wang et al, 200720
Reishi	In vivo, mouse sarcoma 180	IFN-γ TNF-α	TH1 PI	50, 100, 200 mg/kg IP; Ganoderma polysaccharides	Wang et al, 201221
Reishi	Ex vivo, S-180 sarcoma mouse model	IFN-γ IL-4 IL-6	TH1	200 mg/kg IP/d; sporoderms and stipe broken extracts	Yue et al, 200822
Reishi	In vitro, mouse cancer cell line	IL-6 TNF-α	PI	50, 100, 200 mg/mL; broken spores dissolved in water, then extracted with ethanol	Guo et al, 200923
Reishi	In vitro, precancerous uroepithelial cells (HUC-PC cell line)	IL-2 IL-6 NF-κB IL-8	PI	40, 80, 100 mg/mL; ethanol extraction only	Yuen, Gohel, and Ng, 201124
Reishi	In vitro, inflammatory breast cancer cell line	IL-8	PI	0.5, 1.0 mg/mL every 48 h for 96 h; extract of fruiting body and cracked spores	Martinez-Montemayor et al, 201125
Maitake	Ex vivo, human breast cancer participants posttreatment	IFN-γ IL-10 TNF-α	TH1	Dose escalation up to 5 mg/kg PO BID for 21 d; hot water extraction followed by alcohol precipitation, packaged by Gaia Herbs	Deng et al, 200926
Maitake	Ex vivo, mouse colon cancer model	IFN-γ IL-12p70	TH1	7.8 mg/kg/d IP for 19 d; D-fraction of dried maitake	Kodama et al, 200227
Maitake	In vivo, mouse cancer cisplatin treatment	IL-12p70 IL-12p40 IFN-γ G-CSF M-CSF	TH1	8 mg/kg/d IP; water extraction followed by alcohol precipitation, MD-fraction	Masuda et al, 200928
Maitake	In vivo, mouse colon-cancer model	IL-12	TH1	8 mg/kg/d IP; water extraction followed by alcohol precipitation, MD-fraction	Masuda et al, 200829
Maitake	In vivo, mouse carcinoma model	TNF-α IFN-γ IL-12	TH1	5 mg/kg/d PO for 19 d; water extraction followed by alcohol precipitation, D-fraction	Kodama et al, 200230
Maitake	In vivo, mouse carcinoma model	IL-4 IFN-γ IL-12p70 IL-18	TH1 TH2	5 mg/kg/d PO QD for 20 d; D-fraction	Inoue, Kodama, and Nanba, 200231
Maitake	In vivo, mouse colon-cancer model	TNF-α IFN-γ IL-12 IL-1	TH1	7.5, 15.0 mg IP QD for 7 d; hot water extract with an ethanol precipitation, followed by complex gel column fractionations for MLP fraction	Kodama et al, 201032
Maitake	In vivo, mouse colon-cancer model	IFN-γ IL-12p70	TH1	7.8 mg/kg/d IP; hot water extract with an the ethanol precipitation for D fraction	Harada, Kodama, and Nanba, 200333
Maitake	In vitro, human mononuclear cells	IFN-γ TNF-α	TH1	12.5, 11, and 200 mg/mL; intracellular fractions of fruiting body	Svagelj et al, 200834
Cordyceps	In vitro, mouse lymphoma cell line	IL-1 IL-2	PI	200 mg/mL Cordyceps sinensis or 100 mg/mL 1,3-β-glucan	Kawanishi et al, 201035
Turkey Tail	In vivo, TLR2 knockout Mice vs normal mice	IL-12 only in normal mice	TH1	1–100 mg/mL × 96 h; purified PSK	Lu et al, 201136
Turkey Tail	In vitro, breast cancer cell line	TNF-α IFN-γ IL-12	TH1	10 mg/mL; purified PSK	Lu et al, 201137
Turkey Tail	In vitro, TLR2 knockout mice vs normal mice	IFN-γ IL-12p70 TNF-α IL-12p40 IL-2 all inhibited by TLR2 knockout	TH1	1–100 mg/mL × 96 h; purified PSK	Lu et al, 201136

Abbreviations: PO=by mouth; QD=every day; TID=3×/d; IP=intraperitoneal; PSG-1=Ganoderma atrum polysaccharide; BID=2×/d; PSK=polysaccharide K.

Modulation of non-T_H1 cytokines is not as clear-cut. For example, TNF-α is often elevated within in vitro studies, but when it is measured in vivo, it decreases. This result is difficult to interpret and exemplifies the fact that researchers cannot simply study a substance’s immunological activity outside of the organism. The Agaricus, maitake, reishi, Cordyceps, and turkey tail mushrooms often downregulate T_H2 cytokines, which again suggests a benefit in treating cancer. Figure 2 illustrates potential sites of action for constituents of mushrooms that impact immunological pathways in a cancer model.

Figure 2.

Potential Sites of Action

Cellular immunity stimulated through T_H1 responses can be measured in a variety of ways. In addition to examining cytokine patterns, some mushroom studies have examined cellular immunity directly by assessing NK cell and macrophage activity. Increased NK cell killing and phagocytosis can lead to increased tumor destruction. An indirect method of evaluating cellular stimulation is to look at markers of cellular activation. For example, when NK cells are activated, they increase the amount of CD56 and CD69 on their surface. Therefore, increased CD56 and CD69 indicate a beneficial response to cancer. Increasing CD3 suggests an increase of T-cell activity, whereas increasing CD19 is indicative of increasing B cells. The MMP-9 marker is elevated in many cancers and is related to poor prognosis. Thus, mushrooms that downregulate MMP-9 expression would be expected to be beneficial to patients with cancer. Table 4 shows findings from studies using evaluations of cell surface biomarkers and cellular activity to determine how mushrooms activate different cell types.

Table 4.

Cellular Immune Response to Cancer

Mushroom	Model	Cellular Response	Dose	Reference
Agaricus	In vivo, mouse cancer	CD69 and CD49 T cells	350 mg QD; hot water, standardized to 7.2 μg/mL of β-glucan	Takimoto et al, 200815
Agaricus	In vivo, mouse colon cancer	Phagocytosis of spleen cells	100–150 g/d PO; 10% ground, dried mushroom	Ishii et al, 201138
Agaricus	In vivo, mouse leukemia	CD3 CD19 CD11b Liver weight Spleen weight NK activity	3 or 6 mg/kg PO × 3 wk; hot water extract	Lin et al, 201216
Reishi	In vivo, human, late-stage cancer; prospective, nonplacebo-controlled trial with 34 participants	CD56 NK cells	1800 mg PO TID × 3 mo; Ganopoly, hot water extraction, then 75% ethanol extraction, then purified by gel filtration	Gao et al, 200318
Reishi	In vivo, mouse cancer cell line CT26	Phagocytosis via TLR4	50, 100, 200 mg/kg IP; standardized PSG-1 polysaccharide	Zhang et al, 201319
Reishi	In vivo, mouse lung cancer	NK cell activity	50, 100, 200 mg/kg IP × 10 d; kg of ganoderic acid-Me, purified from Ganoderma lucidum	Wang et al, 200720
Reishi	In vivo, mouse sarcoma 180	NK Spleen lymphocytes CD8+ T cells CD4+ T Cells	50, 100, 200 mg/kg IP; Ganoderma polysaccharides	Wang et al, 201221
Reishi	In vivo, mouse leukemia	CD3 CD19 CD11b	3 mg/kg/d or 6 mg/kg/d IP; crude extract	Chang, Yang, and Yang, 200939
Reishi	In vitro, human colon-cancer line HCT-116	Cell growth Cell adhesion MMP-9 NF-κB iNOS	Varied dose; ganoderic acid	Chen et al, 201040
Reishi	In vitro, human hepatoma HepG2 cell line	MMP-9 NF-κB ERK	10, 25, 50, 75, 100 mM; purified lucidenic acid	Weng, Chau, Hsieh, 200841
Reishi	In vitro, MAD-MB-231 human breast cancer cell line	Akt NF-κB	0.25, 0.5, 1 mg/mL; standardized powdered extract (20:1) with spores to 13.5% polysaccharides and 6% triterpenes	Jiang et al, 200442
Reishi	In vitro, human prostate cancer cell line	VEGF TGF-β1	0.25, 0.5 or 1.0 mg/mL × 24 h; ReishiMax brand	Stanley et al, 200543
Reishi	In vitro, MAD-MB-231 human breast cancer cell line	AP-1 NF-κB CDK4 uPA	0.1, 0.25, 0.5 mM; purified ganoderic acid A, F, and H	Jiang et al, 200844
Reishi	In vitro, human inflammatory breast cancer line	MMP-9	0.5, 1.0 mg/mL every 48 h of 96 h; extract of fruiting body and cracked spores	Martinez-Montemayor et al, 201125
Maitake	In vivo, mouse colon cancer	Tumor-specific CD8+ and CD4+ T cells NK cells T-cell infiltration Treg cells	20 or 80 mg/kg PO for 20 d; MD-fraction	Masuda et al, 201345
Maitake	In vivo, BALB/c mice implanted with colon 26 carcinoma cells	CD8+ and CD4+ T cells	7.8 mg/kg/d IP; D-fraction	Harada et al, 200333
Cordyceps	In vitro, human bladder cancer cell lines 5637 and T-24	MMP-9 NF-κB	50, 100, 200 μg/mL; cordycepin	Lee, Kim, and Moon, 201046
Turkey Tail	In vivo, human breast cancer, phase I clinical trial	Lymphocyte count NK activity CD8+ T cells CD19+ B cells	6 or 9 g PO daily for 6 wk	Torkelson et al, 201247

Abbreviations: QD = every day; PO = by mouth; TID = 3 ×/d; PSG-1 = Ganoderma atrum polysaccharide; IP = intraperitoneal.

Mushrooms can affect cancer through immunomodulation resulting in tumor destruction or can have an effect on the tumor directly. Studies that measure direct tumor markers may be indirectly measuring the end result of immunomodulation or directly measuring other factors, such as cell cycle arrest influenced by mushrooms. In Table 5, the effects of mushrooms on tumor volume, angiogenesis, apoptosis, and survival are presented. Of particular note, a derivative of turkey tail mushroom, polysaccharide K (PSK), when administered to stage II/III colorectal patients, was found to be effective.14 PSK was given at 3 g/d for 2 years in conjunction with standard therapy and survival was assessed. The researchers found that the control group had a 60% survival rate compared to 86.8% in the PSK treatment group, a finding that was statistically significant.

Table 5.

Markers of Immune Cell Activation

Mushroom	In vivo/vitro/model	Measure of Immune Activation	Dose	Reference
Agaricus	In vitro, human hepatocarcinoma cell line	% apoptotic cells Cell growth inhibited Intracellular accumulation of doxorubicin	5–100 μg/mL dose-dependent response; Agaricus hot-water extraction with ethanol precipitations and gel chromatography fractionation	Lee and Hong, 201148
Agaricus	In vitro, osteosarcoma cell line	Cell growth	100, 200, 400 μg; purified polysaccharide	Wu et al, 201249
Reishi	In vivo, mouse sarcoma 180	Cell proliferation	50, 100, 200 μg/kg IP; Ganoderma polysaccharides	Wang et al, 201221
Reishi	In vivo, mouse lung cancer model	Splenocyte proliferation Tumor size Tumor growth Tumor metastasis	50, 100, 200 mg/kg IP × 10 d; ganoderic acid-Me purified from Ganoderma lucidum	Wang et al, 200720
Reishi	In vivo, mouse cancer cell line CT26	Tumor growth	50, 100, 200 mg/kg IP; PSG-1 polysaccharide	Zhang et al, 201319
Reishi	In vivo, Lewis lung carcinoma model in mice	Tumor growth	28 mg/kg IP QD × 7 d; ganoderic acid	Chen et al, 201050
Reishi	In vivo, mouse leukemia model	Phagocytosis from PBMC	3 mg/kg/d or 6 mg/kg/d; crude extract	Chang, Yang, and Yang, 200939
Reishi	In vivo, S-180 sarcoma mouse model	Sarcoma size	100, 200, 400 mg/kg IP; hot water extraction of fruiting body, stipe, and sporoderm broken spores	Yue et al, 200822
Reishi	Ehrlich’s ascites carcinoma in mice	Tumor volume by 80.8%	100 mg/kg administered IP 24 h after tumor induction	Joseph et al, 201151
Reishi	In vitro, human prostate-cancer cell line	Angiogenesis	0.25, 0.5 or 1.0 mg/mL × 24 h; ReishiMax proprietary extract	Stanley et al, 200543
Reishi	In vitro, human breast-cancer cell line MDA-MB-231	Cell proliferation	0.1, 0.25, 0.5 mM; purified ganoderic acid A, F, and H	Jiang et al, 200844
Reishi	In vitro, human MAD-MB-231 breast cancer cells	Cell proliferation; complete inhibition at highest dosage	0.25, 0.5, 1.0 mg/mL; standardized powdered extract (20:1) with spores to 13.5% polysaccharides and 6% triterpenes	Jiang et al, 200442
Reishi	In vitro, human inflammatory breast-cancer line	Cell viability Apoptosis BCL-2 TERT PDGFB	0.5, 1.0 mg/mL every 48 h for 96 h; extract of fruiting body and cracked spores	Martinez-Montemayor et al, 201125
Reishi	In vitro, human colon-cancer cell line	Cell growth Cell adhesion	Varied doses; purified ganoderic acid	Chen et al, 201040
Maitake	In vivo, carcinoma-bearing BALB/c mice	Tumor volume	7.8 mg/kg/d IP for 19 d; D-fraction	Kodama et al, 200226
Maitake	In vivo, colon cancer mouse model	Tumor size	20 or 80 mg/kg PO for 20 d; MD-fraction	Masuda et al, 201345
Maitake	In vivo, male C3H/ HeN mice bearing MM-46 carcinoma	Tumor size	5mg/kg/d PO QD for 20 d; D-fraction	Inoue, Kodama and Nanba, 200231
Maitake	In vitro, human prostate cancer cell PC-3	Cell growth 65%	50,000 IU/mL; D-fraction	Pyo et al, 200852
Turkey Tail	In vivo/human stage II or III colorectal cancer	5-y survival (60% control; 86.7% PSK treatment group)	3g/d PO × 2 y; PSK	Ohwada et al, 200614

Abbreviations: IP=intaperitoneal; PSG-1=Ganoderma atrum polysaccharide; QD=every day; PBMC=peripheral blood mononuclear cell; BCL-2=B cell lymphoma 2; TERT=telomerase reverse transcription factor; PDGFB=platelet-derived growth factor-B polypeptide; PO=by mouth; PSK=polysaccharide K.

Few studies examining immunological outcomes have been conducted within the clinical trial framework. That framework is the key to moving the knowledge of mushroom immunology out of the lab and animal models and into both physically well and diseased human populations. A recent phase 1, dose-escalation, clinical trial of turkey tail evaluated dosing safety and immune function in women with breast cancer.47 Turkey tail extract was well-tolerated and was immunomodulatory at higher doses (6 g or 9 g) by increasing CD8+ T cells and CD19+ B cells. The researchers also found that the radiation-induced decline in NK cells was improved by a 6-gram dosing per day of turkey tail.

Agaricus has also been tested by Ohno et al in a phase I clinical study of safety with participants in cancer remission.53 At all doses—1.8, 3.6, and 5.4 g/d for 6 months, Agaricus was well-tolerated, with a 12% rate of adverse events that were digestive in nature, such as nausea. While Agaricus was deemed safe, the study did not follow immune outcomes for the enrolled patients.

Gao et al studied the use of reishi polysaccharides in late-stage cancer patients and late-stage, lung cancer patients.17,18 In participants with late-state lung cancer treated with 5.4 g/d of a proprietary reishi extract (Ganopoly), IL-2, IL-6, and IFN-γ increased. Great variability in patients’ responses occurred, with some participants having a very significant increase while others had minimal changes. This finding suggests that subgroups of patients may respond more favorably to reishi, although the mechanisms of such a difference have not been studied at this time. When Ganopoly was studied in late-stage cancer patients, it was found that a dose of 5.4 g/d increased IL-2, IL-6, and IFN-γ and decreased TNF-α and IL-1. This dosage also increased NK cells (CD56+ cells) and NK activity.

The immune-stimulating impact that mushrooms can exert on NK cells, macrophages, and T cells can also provide a protective effect against chemotherapeutic myelosuppression, one of the most serious deleterious effects of chemotherapy. Because severe myelosuppression neutropenia often truncates treatment and requires hospitalization before full therapeutic effects can be achieved, reducing myelosuppression would allow for better response to chemotherapy.54,55 One promising study examined the effect of the MD-fraction from the maitake mushroom on cisplatin-induced myelosuppression in a mouse model. Mice given 8 mg/kg/d while treated with cisplatin did not experience a decrease in NK cells, DCs, and macrophages. These mice also maintained body weight and spleen weight compared to those treated with cisplatin alone.28 Another study demonstrated that mice that had been immunosuppressed with cyclophosphamide and then subsequently treated with a water-soluble extract from reishi had an increase in red blood cells (RBCs), white blood cells (WBCs), NK T cells, splenic NK cells, and a number of bone marrow cells.56 Given the need to find treatments for this difficult side effect, human studies are needed at this time that examine whether mushrooms are protective against myelosuppression during chemotherapy.

Mushrooms With Antineoplastic Agents

In addition to treating chemotherapeutic myelosuppression, studies have shown that medicinal mushrooms can be used in conjunction with antineoplastic agents to increase the efficacy of chemotherapeutic agents and radiation, the mainstay treatments for most cancers.

Chemotherapy must penetrate the tumor and accumulate within each cell to induce cell cycle arrest and apoptosis. Each of the mushrooms discussed within this review has been shown to increase the effects of chemotherapy, usually by increasing the dose of chemotherapeutic agent that accumulates within a cell (Table 6). For example, when an Agaricus extract high in β-glucan is used in conjunction with doxorubicin, a chemotherapeutic agent, the effectiveness of the drug is increased.48 Doxorubicin combined with Agaricus is accumulated at higher doses within hepatocellular carcinoma cells and increases apoptosis compared to doxorubicin alone.

Table 6.

Mushrooms and Chemotherapeutic Agents

Chemotherapeutic Agent	Indicated Mushroom	Reference
Trastudzumab	PSK (turkey tail)	Lu et al, 2011b37
Cyclophosphamide	Reishi	Zhu et al, 200756
Cisplatin	Maitake, Cordyceps, reishi	Masuda et al, 200928; Yao et al, 201257
Docetaxel	PSK (turkey tail)	Kinoshita et al, 200958; Wenner et al, 201259
Doxorubicin	Agaricus	Lee and Hong, 201148

Abbreviations: PSK = polysaccharide K.

Similarly, PSK extracted from turkey tail increases the efficacy of the drug docetaxel in the treatment of human gastric carcinoma. Within an in vitro and an in vivo model, Kinoshita et al found that PSK inhibited NF-κB, and survivin, an antiapoptotic molecule.58 The researchers were able to use a lower dose of the drug to induce similar levels of apoptosis. Other studies confirm this observation in a human prostate cancer model.59 Extracts from reishi in the form of ganoderic acid A were recently found to increase accumulation of the chemotherapeutic agent cisplatin inside tumor cells. Specifically, ganoderic acid A sensitized the cancer cell line HepG2 to cisplatin by suppressing Janus kinase/signal transducers and activators of transcription (JAK/STAT3), allowing cisplatin to amplify the apoptosis rate.57

Akin to the effects of reishi, cytotoxicity from cisplatin also increased significantly when Cordyceps extract was added.60 To understand the mechanism of this increased cytotoxicity, researchers can examine a study in which Cordyceps was used in an in vitro model of nonsmall-cell lung cancer (NSCLC), a treatment resistant form of cancer that accounts for 80% of that cancer. Cordyceps extract decreased vascular endothelial growth factor (VEGF) and basic fibrogrowth factor (bFGF) in vitro. Thus, Cordyceps can decrease blood supply to the cancer cell and increase the ability of cisplatin to exert cytotoxic effects.

Some anticancer therapies are dependent on NK-cell function to induce apoptosis. One such drug is trastuzumab, a HER2-targeted monoclonal antibody therapy. When PSK from turkey tail was given with trastuzumab, cell-mediated cytotoxicity was greatly increased.37 Interestingly, when PSK and trastuzumab were used alone, they had similar rates of tumor inhibition. Combined, these 2 treatments decreased cell growth in tumors by 96%.

In addition to chemotherapy, researchers are seeking to improve the deleterious side effects of radiation therapy using mushrooms. β-Glucan isolated from reishi significantly improves mouse survival postradiation. Pillai and Devi studied mouse survival, hematology, liver GSH (reduced glutathione), liver malondialdehyde (MDA) and bone marrow chromosomal aberrations in mice exposed to a 4-Gy or 8-Gy radiation dose with or without β-glucan.61 They found that β-glucan rescued 66% of mice from death, compared to 100% mortality when no radioprotective agent was used. When combined with the radioprotective drug amifostine, survival increased to 83%. They also found a significant decrease in bone marrow aberrations in mice pretreated with β-glucan.

Discussion

The evidence base for using mushrooms in cancer treatment has greatly increased in the past 5 years. Many researchers are working to purify and study individual constituents of mushrooms to understand their effects on apoptosis, cell cycle arrest, and immune modulation.62 This research is allowing researchers to move from lab bench to bedside. As this review has demonstrated, mushrooms show great promise as adjunctive treatment used in conjunction with typical care for patients with cancer, as well as treatment to stimulate the immune response to cancer. Research to date has shown a high safety profile of for mushrooms and a lack of negative interactions. As the science continues to emerge, it is likely that the efficacy and safety will justify medicinal mushrooms as an adjunct treatment. Table 7 summarizes potential clinical applications.

Table 7.

Summary of Potential Clinical Applications

Type of Cancer	Indicated Mushroom
Nonsmall-cell lung cancer	Cordyceps
Lung cancer	Reishi
Gastric cancer	PSK (turkey tail)
Hepatocellular carcinoma	Agaricus, reishi
Leukemia	Agaricus, reishi
Lymphoma	Cordyceps
Breast cancer	Reishi, maitake, turkey tail
Colon cancer	Maitake, reishi, turkey tail
Prostate cancer	Reishi
Sarcoma	Reishi

Abbreviations: PSK = polysaccharide K.

The mushrooms discussed in this review elicit effects on cytokine production. The authors know that immune stimulation during cancer can be beneficial in terms of tumor regression and patients’ survival.2 Upon diagnosis, most patients are treated with antineoplastic therapy and are immunosuppressed. Emerging evidence suggests that mushrooms may reverse myelosuppression, which makes them a promising adjunct therapy to optimize overall treatment outcomes.

Anytime an adjunct therapy is added to a conventional therapy, drug-botanical interaction must be addressed. Interestingly, mushrooms appear to increase the effects of chemotherapy. This important finding must be considered when patients are using mushrooms for myelosuppression or other symptoms.

While the immunological findings are promising, ultimately this information must be applied to patients and clinical outcomes, as the goal when working with any patient with cancer is to improve quality of life and ultimately improve survival. To that end, the meta-analysis of turkey tail by Eliza et al demonstrated an increased rate of survival for cancer patients who took this mushroom, especially participants with breast, gastric, and colorectal cancers.63 The articles examined in this meta-analysis did not obtain immunologic outcomes and were thus not included in the current article. Similarly, a retrospective case series of patients who were treated for hepatocellular carcinoma with a combination of 11 different integrative therapies, which included Cordyceps and β-glucan from Agaricus, showed a significant correlation between the number of treatments used and survival. Patients given ≥4 agents had a survival of 40.2 vs 6.4 months for those given ≤3 agents (P < .001). Of these individuals, participants whose combination therapy included Cordyceps had the longest survival.64

Conclusions

As the treatment of various cancers continues to evolve, mushrooms should be considered as an adjunct therapy. As with any phytochemical, the dose, concentration, absorption, and extraction methods play a role in the pharmacological effects, and these factors will be important in future studies. With more research and a better understanding of how different mushrooms elicit varied effects, it will be increasingly important that integrative clinicians work with oncologists to determine the appropriate treatment for each individual. Research into underlying mechanisms of mushrooms will continue to help in devising new strategies for treating cancer, preventing its long-term complications, and increasing survival.