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Non-prescriptional use of medicinal herbs among cancer patients is common around the world. The alleged anti-cancer effects of most herbal extracts are mainly based on studies derived from in vitro or in vivo animal experiments. The current information suggests that these herbal extracts exert their biological effect either through cytotoxic or immunomodulatory mechanisms. One of the active compounds responsible for the immune effects of herbal products is in the form of complex polysaccharides known as beta-glucans. beta-glucans are ubiquitously found in both bacterial or fungal cell walls and have been implicated in the initiation of anti-microbial immune response. Based on in vitro studies, beta-glucans act on several immune receptors including Dectin-1, complement receptor (CR3) and TLR-2/6 and trigger a group of immune cells including macrophages, neutrophils, monocytes, natural killer cells and dendritic cells. As a consequence, both innate and adaptive response can be modulated by beta-glucans and they can also enhance opsonic and non-opsonic phagocytosis. In animal studies, after oral administration, the specific backbone 1-->3 linear beta-glycosidic chain of beta-glucans cannot be digested. Most beta-glucans enter the proximal small intestine and some are captured by the macrophages. They are internalized and fragmented within the cells, then transported by the macrophages to the marrow and endothelial reticular system. The small beta-glucans fragments are eventually released by the macrophages and taken up by other immune cells leading to various immune responses. However, beta-glucans of different sizes and branching patterns may have significantly variable immune potency. Careful selection of appropriate beta-glucans is essential if we wish to investigate the effects of beta-glucans clinically. So far, no good quality clinical trial data is available on assessing the effectiveness of purified beta-glucans among cancer patients. Future effort should direct at performing well-designed clinical trials to verify the actual clinical efficacy of beta-glucans or beta-glucans containing compounds.
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BioMed Central
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Journal of Hematology & Oncology
Open Access
Review
The effects of β-glucan on human immune and cancer cells
Godfrey Chi-Fung Chan*1, Wing Keung Chan1 and Daniel Man-Yuen Sze2
Address: 1Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong and
2Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong
Email: Godfrey Chi-Fung Chan* - gcfchan@hkucc.hku.hk; Wing Keung Chan - wingkc@graduate.hku.hk; Daniel Man-
Yuen Sze - daniel.sze@polyu.edu.hk
* Corresponding author
Abstract
Non-prescriptional use of medicinal herbs among cancer patients is common around the world.
The alleged anti-cancer effects of most herbal extracts are mainly based on studies derived from in
vitro or in vivo animal experiments. The current information suggests that these herbal extracts
exert their biological effect either through cytotoxic or immunomodulatory mechanisms. One of
the active compounds responsible for the immune effects of herbal products is in the form of
complex polysaccharides known as β-glucans. β-glucans are ubiquitously found in both bacterial or
fungal cell walls and have been implicated in the initiation of anti-microbial immune response. Based
on in vitro studies, β-glucans act on several immune receptors including Dectin-1, complement
receptor (CR3) and TLR-2/6 and trigger a group of immune cells including macrophages,
neutrophils, monocytes, natural killer cells and dendritic cells. As a consequence, both innate and
adaptive response can be modulated by β-glucans and they can also enhance opsonic and non-
opsonic phagocytosis. In animal studies, after oral administration, the specific backbone 13 linear
β-glycosidic chain of β-glucans cannot be digested. Most β-glucans enter the proximal small
intestine and some are captured by the macrophages. They are internalized and fragmented within
the cells, then transported by the macrophages to the marrow and endothelial reticular system.
The small β-glucans fragments are eventually released by the macrophages and taken up by other
immune cells leading to various immune responses. However, β-glucans of different sizes and
branching patterns may have significantly variable immune potency. Careful selection of appropriate
β-glucans is essential if we wish to investigate the effects of β-glucans clinically. So far, no good
quality clinical trial data is available on assessing the effectiveness of purified β-glucans among cancer
patients. Future effort should direct at performing well-designed clinical trials to verify the actual
clinical efficacy of β-glucans or β-glucans containing compounds.
Introduction
A significant proportion of cancer patients have been tak-
ing complementary medical therapies while receiving
their conventional anti-cancer treatments [1-6]. Among
them, herbal extracts such as Ganoderma lucidum are one
of the most common modalities being consumed espe-
cially among Oriental [7-10]. Two mechanisms have been
proposed to be responsible for the anti-cancer action of
these herbal extracts; one is via direct cytotoxic effect and
the other is indirectly through immunomodulatory action
[11,12]. Many cytotoxic chemotherapeutic agents cur-
rently in use such as vincristine, taxol and etoposide are
Published: 10 June 2009
Journal of Hematology & Oncology 2009, 2:25 doi:10.1186/1756-8722-2-25
Received: 30 December 2008
Accepted: 10 June 2009
This article is available from: http://www.jhoonline.org/content/2/1/25
© 2009 Chan et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Journal of Hematology & Oncology 2009, 2:25 http://www.jhoonline.org/content/2/1/25
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originally purified from herbs. On the other hand, herbs
with immunomodulatory functions have mainly been
advocated by commercial sectors and most of them can be
directly purchased over the counter or the internet. Unfor-
tunately, organized efforts to investigate the actual useful-
ness of this group of herbs as well as their active
ingredients are lacking. In recent years, one of the active
ingredients responsible for the immunomodulation of
many of these herbs was found to be a form of complex
polysaccharides known as "β-D-glucan", or simply called
β-glucan [8,13]. The receptors and mechanisms of action
of β-glucans have recently been unfolded via in vitro and
in vivo animal experiments. Since β-glucans are inexpen-
sive and have good margin of safety based on historical
track records, their potential therapeutic value deserve fur-
ther investigation. We reviewed here the literature and our
experience on the in vitro and in vivo animal biological
studies of β-glucans, particularly on their immune and
anti-cancer mechanisms.
Physical and chemical properties of
β
-glucan
β-glucans are one of the most abundant forms of polysac-
charides found inside the cell wall of bacteria and fungus.
All β-glucans are glucose polymers linked together by a
1 3 linear β-glycosidic chain core and they differ from
each other by their length and branching structures [14]
(Figure 1). The branches derived from the glycosidic chain
core are highly variable and the 2 main groups of branch-
ing are 14 or 16 glycosidic chains. These branching
assignments appear to be species specific, for example, β-
glucans of fungus have 16 side branches whereas those
of bacteria have 14 side branches. The alignments of
branching follow a particular ratio and branches can arise
from branches (secondary branches). In aqueous solu-
tion, β-glucans undergo conformational change into tri-
ple helix, single helix or random coils. The immune
functions of β-glucans are apparently dependent on their
conformational complexity [15]. It has been suggested
that higher degree of structural complexity is associated
with more potent immunmodulatory and anti-cancer
effects.
For research purposes, the composition or structural
information of β-glucans can be evaluated by a variety of
methods including liquid chromatography/mass spec-
trometry (LC/MS)[16], high performance liquid chroma-
tography (HPLC)[17] and less often X-ray crystallography
[18] or atomic force microscopy [19]. However, due to the
tedious and lack of quantitative nature of most of these
technical methods, they cannot be applied routinely as a
screening tool. Other less sophisticated techniques in
studying the β-glucans contents include phenol-sulphuric
acid carbohydrate assay, aniline blue staining method and
ELISA. Because chemical modification invariably induces
changes in the natural conformation, most of these meth-
ods cannot reflect the genuine relationship between the
structure and the bioactivity. Among them, aniline blue
staining method is a relatively simple method to screen
for β-glucan because of its ability to retain the natural con-
formation of β-glucans during the staining process. It also
has a good specificity for β-glucans but its limitation is
that it can only measure the core 13 linear glycosidic
chain and not the branches.
Endotoxin contamination is another important issue
affecting the safety and potential biological effect of β-glu-
can. Lipopolysaccharide (LPS) is an endotoxin found
inside the Gram negative bacterial cell wall and consists of
three main parts including lipid A, core and polysaccha-
ride chain [20]. Among them, lipid A was found to be the
major component that can initiate an immune response.
LPS contamination can occur during the culture or prepa-
ration of β-glucans. Since LPS is one of the most potent
immune stimulator and its contamination can lead to
false positive results in immune tests, quantification of
LPS should be performed, which can be evaluated by
either the rabbit pyrogen test or the modified limulus
amebocyte lysate (LAL) assay with devoid factor G [21].
Pharmacodynamics & Pharmacokinetics of
β
-glucan
Most β-glucans are considered as non-digestible carbohy-
drates and are fermented to various degrees by the intesti-
nal microbial flora [22-24]. Therefore, it has been
speculated that their immunomodulatory properties may
be partly attributed to a microbial dependent effect. How-
ever, β-glucans in fact can directly bind to specific recep-
tors of immune cells, suggesting a microbial independent
immunomodulatory effect [25]. The pharmacodynamics
and pharmacokinetics of β-glucans have been studied in
animal and human models.
Animal Studies
Study using a suckling rat model for evaluation of the
absorption and tissues distribution of enterally adminis-
tered radioactive labeled β-glucan, it was found that the
majority of β-glucan was detected in the stomach and
duodenum 5 minutes after the administration [26]. This
amount rapidly decreased during first 30 minutes. A sig-
nificant amount of β-glucan entered the proximal intes-
tine shortly after ingestion. Its transit through the
proximal intestine decreased with time with a simultane-
ous increase in the ileum. Despite low systemic blood lev-
els (less than 0.5%), significant systemic
immunomodulating effects in terms of humoral and cel-
lular immune responses were demonstrated.
The pharmacokinetics following intravenous administra-
tion of 3 different highly purified and previously charac-
terized β-glucans were studied using carbohydrates
covalently labeled with a fluorophore on the reducing ter-
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minus. The variations in molecular size, branching fre-
quency and solution conformation were shown to have
an impact on the elimination half-life, volume of distribu-
tion and clearance [27].
The low systemic blood level of β-glucans after ingestion
does not reflect the full picture of the pharmacodynamics
of β-glucans and does not rule out its in vivo effects. Che-
ung-VKN et al. labeled β-glucans with fluorescein to track
their oral uptake and processing in vivo. The orally admin-
istered β-glucans were taken up by macrophages via the
Dectin-1 receptor and was subsequently transported to
the spleen, lymph nodes, and bone marrow. Within the
bone marrow, the macrophages degraded the large β-1,3-
glucans into smaller soluble β-1,3-glucan fragments.
These fragments were subsequently taken up via the com-
β-glucan is one of the key components of the fungal cell wallFigure 1
β-glucan is one of the key components of the fungal cell wall. The basic subunit of the fungal β-glucan is β-D-glucose
linked to one another by 13 glycosidic chain with 16 glycosidic branches. The length and branches of the β-glucan from
various fungi are widely different.
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plement receptor 3 (CR3) of marginated granulocytes.
These granulocytes with CR3-bound β-glucan-fluorescein
were shown to kill inactivated complement 3b (iC3b)-
opsonized tumor cells after they were recruited to a site of
complement activation such as tumor cells coated with
monoclonal antibody [28] (Figure 2). It was also shown
that intravenous administered soluble β-glucans can be
delivered directly to the CR3 on circulating granulocytes.
Furthermore, Rice PJ et al. showed that soluble β-glucans
such as laminarin and scleroglucan can be directly bound
and internalized by intestinal epithelial cells and gut asso-
ciated lymphoid tissue (GALT) cells [29]. Unlike macro-
phage, the internalization of soluble β-glucan by
intestinal epithelial cells is not Dectin-1 dependent. How-
ever, the Dectin-1 and TLR-2 are accountable for uptake of
soluble β-glucan by GALT cells. Another significant find-
ing of this study is that the absorbed β-glucans can
increase the resistance of mice to bacterial infection chal-
lenge.
Human Studies
How β-glucans mediate their effects after ingestion in
human remained to be defined. In a phase I study for the
assessment of safety and tolerability of a soluble form oral
β-glucans [30]. β-glucans of different doses (100 mg/day,
200 mg/day or 400 mg/day) were given respectively for 4
consecutive days. No drug-related adverse events were
observed. Repeated measurements of β-glucans in serum,
however, revealed no systemic absorption of the agent fol-
lowing the oral administration. Nonetheless, the immu-
noglobulin A concentration in saliva increased
significantly for the 400 mg/day arm, suggesting a sys-
temic immune effect has been elicited. One limitation of
this study is the low sensitivity of serum β-glucans deter-
mination.
In summary, based on mostly animal data, β-glucans
enter the proximal small intestine rapidly and are cap-
tured by the macrophages after oral administration. The β-
glucans are then internalized and fragmented into smaller
sized β-glucans and are carried to the marrow and
endothelial reticular system. The small β-glucans frag-
ments are then released by the macrophages and taken up
by the circulating granulocytes, monocytes and dendritic
cells. The immune response will then be elicited. How-
ever, we should interpret this information with caution as
most of the proposed mechanisms are based on in vitro
The uptake and subsequent actions of β-glucan on immune cellsFigure 2
The uptake and subsequent actions of β-glucan on immune cells. β-glucans are captured by the macrophages via the
Dectin-1 receptor with or without TLR-2/6. The large β-glucan molecules are then internalized and fragmented into smaller
sized β-glucan fragments within the macrophages. They are carried to the marrow and endothelial reticular system and subse-
quently released. These small β-glucan fragments are eventually taken up by the circulating granulocytes, monocytes or macro-
phages via the complement receptor (CR)-3. The immune response will then be turned on, one of the actions is the
phagocytosis of the monoclonal antibody tagged tumor cells.
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and in vivo animal studies. Indeed, there is little to no evi-
dence for these hypothesized mechanisms of action and
pharmacokinetics occurred in human subjects at the
moment.
β
-glucans as immunomodulating agent
Current data suggests that β-glucans are potent immu-
nomodulators with effects on both innate and adaptive
immunity. The ability of the innate immune system to
quickly recognize and respond to an invading pathogen is
essential for controlling infection. Dectin-1, which is a
type II transmembrane protein receptor that binds β-1,3
and β-1,6 glucans, can initiate and regulate the innate
immune response [31-33]. It recognizes β-glucans found
in the bacterial or fungal cell wall with the advantage that
β-glucans are absent in human cells. It then triggers effec-
tive immune responses including phagocytosis and proin-
flammatory factors production, leading to the elimination
of infectious agents [34,35]. Dectin-1 is expressed on cells
responsible for innate immune response and has been
found in macrophages, neutrophils, and dendritic cells
[36]. The Dectin-1 cytoplasmic tail contains an immu-
noreceptor tyrosine based activation motif (ITAM) that
signals through the tyrosine kinase in collaboration with
Toll-like receptors 2 and 6 (TLR-2/6) [34,37,38]. The
entire signaling pathway downstream to dectin-1 activa-
tion has not yet been fully mapped out but several signal-
ing molecules have been reported to be involved. They are
NF-κB (through Syk-mediate pathway), signaling adaptor
protein CARD9 and nuclear factor of activated T cells
(NFAT) [39-41] (Fig. 3). This will eventually lead to the
release of cytokines including interleukin (IL)-12, IL-6,
tumor necrosis factor (TNF)-α, and IL-10. Some of these
cytokines may play important role in the cancer therapy.
On the other hand, the dendritic cell-specific ICAM-3-
grabbing non-integrin homolog, SIGN-related 1
(SIGNR1) is another major mannose receptor on macro-
phages that cooperates with the Dectin-1 in non-opsonic
recognition of β-glucans for phagocytosis [42] (Fig 3).
Furthermore, it was found that blocking of TLR-4 can
inhibit the production of IL-12 p40 and IL-10 induced by
purified Ganoderma glucans (PS-G), suggesting a vital
role of TLR-4 signaling in glucan induced dendritic cells
maturation. Such effect is also operated via the augmenta-
tion of the IκB kinase, NF-κB activity and MAPK phospho-
rylation [43]. One additional point to note is that those
studies implied the interaction between β-glucans and
TLR all used non-purified β-glucans, therefore the actual
involvement of pure β-glucans and TLR remains to be
proven.
Other possible receptors and signaling pathways induced
by β-glucans are less definite at the moment. For example,
lentinan, a form of mushroom derived β-glucans, has
been found to bind to scavenger receptor found on the
surface of myeloid cells and triggers phosphatidylinositol-
3 kinase (PI3K), Akt kinase and p38 mitogen-activated
protein kinase (MAPK) signaling pathway [44](Fig. 3).
But no specific β-glucans scavenger receptor has been
identified so far. Candida albicans derived β-glucans but
not other forms of pathogenic fungal β-glucans can bind
to LacCer receptor and activate the PI-3K pathway in con-
trolling the neutrophil migration [45] (Fig. 3), but such
activation pathway may involve other molecules found in
the Candida derived β-glucans.
We found that β-glucans can induce human peripheral
blood mononuclear cells proliferation [46]. It can also
enhance phenotypic and functional maturation of mono-
cyte derived dendritic cells with significant IL-12 and IL-
10 production. Similar findings were found by Lin et al.
using PS-G, in addition, treatment of dendritic cells with
PS-G resulted in enhanced T cell-stimulatory capacity and
increased T cell secretion of interferon-γ and IL-10
[43,47]. This action is at least mediated in part through
the Dectin-1 receptor. The potency of such immunomod-
ulating effects differs among β-glucans and purified
polysaccharides of different size and branching complex-
ity. In general, bigger size and more complex β-glucans
such as those derived from Ganoderma lucidum have
higher immunomodulating potency.
The adaptive immune system functions through the com-
bined action of antigen-presenting cells and T cells. Spe-
cifically, class I major histocompatibility complex (MHC-
I) antigen presentation to CD8(+) cytotoxic T cells is lim-
ited to proteosome-generated peptides from intracellular
pathogens. On the other hand, the class II MHC (MHC-II)
endocytic pathway presents only proteolytic peptides
from extracellular pathogens to CD4(+) T helper cells.
Carbohydrates have been previously thought to stimulate
immune responses independently of T cells [48]. How-
ever, zwitterionic polysaccharides (polysaccharides that
carry both positive and negative charges) such as β-glu-
cans can activate CD4(+) T cells through the MHC-II
endocytic pathway [49]. β-glucans are processed to low
molecular weight carbohydrates by a nitric oxide-medi-
ated mechanism. These carbohydrates will then bind to
MHC-II inside antigen-presenting cells such as dendritic
cells for presentation to T helper cells. Initial data sug-
gested that it subsequently leads to Th-1 response, but
there are conflicting data related to this aspect. In our in
vitro data, β-glucans do not tend to polarize T cells into
either Th-1, Th-2 or regulatory T cells [46]. However,
recent publications suggested β-glucans such as zymosan
may induce T-cells into T-reg cells in a NOD mice model
[50]. Therefore, whether β-glucans can induce important
immunologic responses through T cell activation remain
to be further investigated.
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Immune activation induced by β-glucansFigure 3
Immune activation induced by β-glucans. β-glucans can act on a variety of membrane receptors found on the immune
cells. It may act singly or in combine with other ligands. Various signaling pathway are activated and their respective simplified
downstream signaling molecules are shown. The reactors cells include monocytes, macrophages, dendritic cells, natural killer
cells and neutrophils. Their corresponding surface receptors are listed. The immunomodulatory functions induced by β-glucans
involve both innate and adaptive immune response. β-glucans also enhance opsonic and non-opsonic phagocytosis and trigger a
cascade of cytokines release, such as tumor necrosis factor(TNF)-α and various types of interleukins (ILs).
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Another mechanism of β-glucan action is mediated via
the activated complement receptor 3 (CR3, also known as
CD11b/CD18), which is found on natural killer (NK)
cells, neutrophils, and lymphocytes. This pathway is
responsible for opsonic recognition of β-glucans leading
to phagocytosis and reactor cells lysis. β-glucans bind to
the lectin domain of CR3 and prime it for binding to inac-
tivated complement 3b (iC3b) on the surface of reactor
cells. The reactor cells can be of any cell type including
cancer cells tagged with monoclonal antibody and coated
with iC3b. The β-glucans-activated circulating cells such
as the CR3 containing neutrophils will then trigger cell
lysis on iC3b-coated tumor cells [28]. Similarly, majority
of the human NK cells express CR3 and it was shown that
opsonization of NK cells coated with iC3b leads to an
increase in the lysis of the target. The beta chain of the
CR3 molecule (CD18) rather than the alpha chain
(CD11b) is responsible to the β-glucan binding [51,52].
This concept was supported by in vivo study demonstrat-
ing barley β-1,3;1,4-glucan given orally can potentiate the
activity of an antitumor monoclonal antibody (anti-gan-
glioside-2 or "3F8"), leading to enhanced tumor regres-
sion and survival on a human neuroblastoma xenografts
mouse model [53]. 3F8 plus β-glucan was shown to pro-
duce near-complete tumor regression or disease stabiliza-
tion whereas 3F8 or β-glucan alone showed no significant
effect. The median survival of the 3F8 plus β-glucan group
was 5.5-fold higher than that of the control groups, and
up to 47% of the mice remained progression free in con-
trast to <3% of controls at the end of the study period. No
toxicities were noted in all mice treated with β-glucan,
3F8, or 3F8 plus β-glucan.
A similar xenograft model was adopted subsequently for
investigating various targeted tumor antigens and tumor
types. It was found that β-glucan exerts similar anti-tumor
effects irrespective of antigens (GD2, GD3, CD20, epider-
mal growth factor-receptor, and HER-2) or human tumor
types (neuroblastoma, melanoma, lymphoma, epider-
moid carcinoma, and breast carcinoma) or tumor sites
(subcutaneous versus systemic). The effect was correlated
with the molecular size of the β-1,3;1,4-glucan [53,54].
Furthermore, 2 other receptors known as scavenger [55]
and lactosylceramide [56,57] also bind β-glucans and can
elicit a range of responses. β-glucans can enhance endo-
toxin clearance via scavenger receptors by decreasing TNF
production leading to improved survival in rats subjected
to Escherichia coli sepsis [58]. On the other hand, β-glu-
cans binding to lactosylceramide receptor can enhance
myeloid progenitor proliferation and neutrophil oxida-
tive burst response, leading to an increase in leukocyte
anti-microbial activity. It is also associated with the activa-
tion of NF-κB in human neutrophils [59]. Again in other
studies, structurally different β-glucans appear to have dif-
ferent affinity toward these receptors. For example, only
high molecular weight β-glucans can effectively bind to
the lactosylceramide receptor. Therefore, markedly differ-
ent host responses induced by different β-glucans are
expected.
In summary, β-glucans act on a diversity of immune
related receptors in particularly Dectin-1 and CR3, and
can trigger a wide spectrum of immune responses. The tar-
geted immune cells of β-glucans include macrophages,
neutrophils, monocytes, NK cells and dendritic cells (Fig-
ure 3). The immunomodulatory functions induced by β-
glucans involve both innate and adaptive immune
response. β-glucans also enhance opsonic and non-
opsonic phagocytosis. Whether β-glucans polarize the T
cells subset towards a particular direction remains to be
explored.
Anti-cancer effects of
β
-glucans
It is becoming clear that β-glucans themselves have no
direct cytotoxic effects. Studies implicating the cytotoxic
effects of β-glucans were either from studies using crude
extracts of β-glucan containing herbs or the use of β-glu-
can primed monocytes. For β-glucan containing herbs like
Ganoderma lucidum (Lingzhi), there are other active com-
ponents such as ganoderic acid from its mycelium [60]
and triterpenes from its spore [61-63], which have all
been shown to have direct anti-cancer effects independ-
ently. We did not find any direct cytotoxic effects of β-glu-
cans on a panel of common cancer cell lines tested
including carcinoma, sarcoma, and blastoma. β-glucans
also did not trigger any apoptotic pathways and had no
direct effect on the telomerase and telomeric length of the
cancer cells (unpublished data). In contrast, it stimulated
the proliferation of monocytic lineage leukemic cells in-
vitro and can facilitate the maturation of dendritic cells
derived from leukaemic cells [64]. Hence, whether it is
beneficial to apply β-glucans on leukemic patients
remains controversial and has to be considered with cau-
tion.
In the English literature, there are no clinical trials that
directly assessed the anti-cancer effects of purified β-glu-
cans in cancer patients. Most studies were assessing the
toxicity profile or underlying immune changes of the can-
cer patients without addressing on the change of cancer
status. In addition, most of the related studies used either
crude herbal extracts or a fraction of the extracts instead of
purified β-glucans. Therefore, it is difficult to identify
whether the actual effects were related to β-glucans or
other confounding chemicals found in the mixture.
In a prospective clinical trial of short term immune effects
of oral β-glucan in patients with advanced breast cancer,
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23 female patients with advanced breast cancer were com-
pared with 16 healthy females control [65]. Oral β-
1,3;1,6-glucan was taken daily. Blood samples were recol-
lected on the day 0 and 15. It was found that despite a rel-
atively low initial white cell count, oral β-glucan can
stimulate proliferation and activation of peripheral blood
monocytes in patients with advanced breast cancer.
Whether that can be translated into clinical benefit
remains unanswered.
Clinical trials on anti-cancer effects of natural products
with
β
-glucan
Many edible fungi particularly in the mushroom species
yield immunogenic substances with potential anticancer
activity [66]. β-glucans are one of the common active
components (Table 1). In limited clinical trials on human
cancers, most were well tolerated. Among them, lentinan
derived from Lentinus edodes is a form of β-glucans [67].
Since it has poor enteric absorption, intrapleural, intra-
peritoneal [68] or intravenous routes had been adopted in
clinical trials which showed some clinical benefit when
used as an adjuvant to chemotherapy [69]. Schizophyllan
(SPG) or sizofiran is another β-glucan derived from Schiz-
ophyllan commune. Its triple helical complex β-glucans
structure prevents it from adequate oral absorption so an
intratumoral route or injection to regional lymph nodes
had been adopted [70,71]. In a randomized trial, SPG
combined with conventional chemotherapy improved
the long term survival rate of patients with ovarian cancer
[72]. But whether the prolonged survival can subse-
quently led to a better cure rate remain unanswered.
Maitake D-Fraction extracted from Grifola frondosa
(Maitake mushroom) was found to decrease the size of
the lung, liver and breast tumors in >60% of patients
when it was combined with chemotherapy in a 2 arms
control study comparing with chemotherapy alone [73].
The effects were less obvious with leukemia, stomach and
brain cancer patients [74]. But the validity of the clinical
study was subsequently questioned by another independ-
ent observer [75]. Two proteoglycans from Coriolus versi-
color (Yun Zhi) – PSK (Polysaccharide-K) and PSP
(Polysaccharopeptide) – are among the most extensively
studied β-glucan containing herbs with clinical trials
information. However, both PSK and PSP are protein-
bound polysaccharides, so their actions are not necessary
directly equivalent to pure β-glucans [76]. In a series of tri-
als from Japan and China, PSK and PSP were well toler-
ated without significant side effects [66,77-81]. They also
prolonged the survival of some patients with carcinoma
and non-lymphoid leukemia.
Ganoderma polysaccharides are β-glucans derived from
Ganoderma lucidum (Lingzhi, Reishi). While β-glucan is
the major component of the Ganoderma mycelium, it is
only a minor component in the Ganoderma spore [7].
The main active ingredient in the Ganoderma spore extract
is triterpenoid which is cytotoxic in nature. In an open-
label study on patients with advanced lung cancer, thirty-
six patients were treated with 5.4 g/day Ganoderma
polysaccharides for 12 weeks with inconclusive variable
and results on the cytokines profiles [82]. Another study
on 47 patients with advanced colorectal cancer using the
Table 1: Selected Medicinal Mushroom with β-glucans as Active Components
Herbs Common Name β-glucans structure Types of β-glucans
Lentinus edodes Shiitake mushroom β-1,3;1,6-glucan Lentinan
Schizophyllan commune Brazilian mushroom, Schizophyllan β-1,3;1,6-glucan Schizophyllan (SPG) or sizofiran
Grifola frondosa Maitake mushroom β-1,3;1,6-glucan with xylose and
mannose
Maitake D-Fraction
Coriolus versicolor Yun Zhi Protein bound β-1,3;1,6-glucan PSP (polysaccharide peptide) PSK
(polysaccharide-Kureha or polysaccharide-K,
krestin)
Ganoderma lucidum Lingzhi, Reishi β-1,3;1,6-glucan Ganoderma polysaccharides, Ganopoly
Agaricus blazei Brazilian sun-mushroom,
Himematsutake mushroom
Protein bound β-1,6-glucan Agaricus polysaccharides
Pleurotus ostreatus Oyster mushroom, píng gû β-1,3-glucan with galactose and
mannose
Pleuran
Coprinus comatus Shaggy ink cap, lawyer's wig, or
shaggy mane
β-1,3-glucan Coprinus polysaccharides
Journal of Hematology & Oncology 2009, 2:25 http://www.jhoonline.org/content/2/1/25
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same dosage and period again demonstrated similar vari-
able immune response patterns [83]. These results high-
light the inconsistency of clinical outcomes in using
immune enhancing herbal extracts clinically, which may
partly be due to the impurity of the products used.
Conclusion
The intrinsic differences of the β-glucans derived from dif-
ferent sources will elicit variable immune and anti-cancer
responses. We summarized the current limitations of β-
glucan research from the literature (Table 2). The limita-
tions are further complicated by the fact that many studies
on β-glucan related herbs often used crude extracts rather
than purified compounds, therefore the confounding
effects of other chemicals cannot be totally ruled out [84].
Careful selection of appropriate β-glucan products with
good pre-test quality control is essential if we want to
understand and compare the results on how β-glucans act
on our immune system and exerting anti-cancer effects. A
possibly well-defined β-glucan standard is urgently
needed in this field for controlled experiments. So far,
there are very few clinical trial data on using purified β-
glucans for cancer patients. Future studies should aim to
obtain such information so it can assist us in applying β-
glucans rationally and effectively to our cancer patients in
the future.
Competing interests
The authors declare that there is no conflict of interests,
including conflicts of financial nature involving any phar-
maceutical or commercial company.
Authors' contributions
GCFC initiated the concept, wrote and revised the manu-
script and creating the illustrations. WKC involved in writ-
ing, coordination and revising the manuscript. DMS
involved in the preparation and revision of manuscript.
Acknowledgements
We would like to thank Dr. Anita Chan (U. Alberta) for the English editing,
Mr. Spencer Ng for the production of the graphic figures, the Edward Sai-
Kim Hotung Paediatric Education & Research Fund, URC/CRCG Grants
and Pau Kwong Wun Charitable Foundation for supporting the beta-glucan
related works.
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... The cell walls of S. cerevisiae cells account for 30% of their dry weight and are composed of β-glucan, mannan, protein, lipid, and chitin [3,4]. β-glucan is one of the most common polysaccharides found in the cell walls of bacteria, yeast, and fungi [5]. It is composed of a β(1 → 3)glucan backbone with a β(1 → 6)-glucan side chain [4]. ...
... β-Glucan and mannoprotein compose the majority of yeast cell wall components [40]. β-glucan, a glucose polymer linked by 1 → 3 linear glycosidic bonds, has various lengths and branching structures [5]. Mannoprotein stimulates angiogenesis in endothelial cells via the Erk/ Akt/eNOS signaling pathway [11]. ...
... Mannoprotein stimulates angiogenesis in endothelial cells via the Erk/ Akt/eNOS signaling pathway [11]. The structural complexity of β-glucan determines its functionality [5]. β-glucan has a variety of biological activities, including alleviation of cardiovascular disease, dyslipidemia, and obesity [10]. ...
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Despite a well-known association between gut barrier defect (leaky gut) and several diseases, data on translocation of pathogen molecules, including bacterial DNA (blood bacteriome), lipopolysaccharide (LPS), and serum (1→3)-β-D-glucan (BG), from the gut to the blood circulation (gut translocation) in dengue are still less studied. Perhaps, dengue infection might induce gut translocation of several pathogenic molecules that affect the disease severity. At the enrollment, there were 31 dengue cases in febrile and critical phases at 4.1 ± 0.3 days and 6.4 ± 1.1 days of illness, respectively, with the leaky gut as indicated by positive lactulose-to-mannitol excretion ratio. With blood bacteriome, the patients with critical phase (more severe dengue; n = 23) demonstrated more predominant abundance in Bacteroidetes and Escherichia spp. with the lower Bifidobacteria when compared with the healthy control (n = 5). Meanwhile, most of the blood bacteriome results in dengue with febrile stage (n = 8) were comparable to the control, except for the lower Bifidobacteria in dengue cases. Additionally, endotoxemia at the enrollment was demonstrated in five (62.5%) and 19 (82.6%) patients with febrile and critical phases, respectively, while serum BG was detectable in two (25%) and 20 (87%) patients with febrile and critical phases, respectively. There were higher peripheral blood non-classical monocytes and natural killer cells (NK cells) at the enrollment in patients with febrile phage than in the cases with critical stage. Then, non-classical monocytes (CD14-CD16+) and NK cells (CD56+CD16-) increased at 4 and 7 days of illness in the cases with critical and febrile stages, respectively, the elevation of LPS and/or BG in serum on day 7 was also associated with the increase in monocytes, NK cells, and cytotoxic T cells. In summary, enhanced Proteobacteria (pathogenic bacteria from blood bacteriomes) along with increased endotoxemia and serum BG (leaky gut syndrome) might be collaborated with the impaired microbial control (lower non-classical monocytes and NK cells) in the critical cases and causing more severe disease of dengue infection.
... Lentinan (LNT), which is a purified β-1,3-glucan with β-1,6-branches isolated from Lentinus edodes. LNT, which is known for its immune activity like other β-glucans from medicinal mushrooms (1)(2)(3), has been reported as an intravenous antitumor polysaccharide via enhancement of the host immune system (4). The clinical efficacy of LNT, such as its effect on long-term survival and improvement of life quality, has been confirmed in cancer patients (5,6). ...
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Previous studies demonstrated Ganoderma lucidum polysaccharides (GL-PS), a form of bioactive beta-glucan can stimulate the maturation of monocyte-derived dendritic cells (DC). The question of how leukemic cells especially in monocytic lineage respond to GL-PS stimuli remains unclear. In this study, we used in vitro culture model with leukemic monocytic cell-lines THP-1 and U937 as monocytic effectors cells for proliferation responses and DCs induction. We treated the THP-1 and U937 cells with purified GL-PS (100 microg/mL) or GL-PS with GM-CSF/IL-4. GL-PS alone induced proliferative response on both THP-1 and U937 cells but only THP-1 transformed into typical DC morphology when stimulated with GL-PS plus GM-CSF/IL-4. The transformed THP-1 DCs had significant increase expression of HLA-DR, CD40, CD80 and CD86 though not as high as the extent of normal monocyte-derived DCs. They had similar antigen-uptake ability as the normal monocyte-derived DCs positive control. However, their potency in inducing allogeneic T cell proliferation was also less than that of normal monocyte-derived DCs. Our findings suggested that GL-PS could induce selected monocytic leukemic cell differentiation into DCs with immuno-stimulatory function. The possible clinical impact of using this commonly used medicinal mushroom in patients with monocytic leukemia (AML-M4 and M5) deserved further investigation.
Book
Since the publication of the first edition, important developments have emerged in modern mushroom biology and world mushroom production and products. The relationship of mushrooms with human welfare and the environment, medicinal properties of mushrooms, and the global marketing value of mushrooms and their products have all garnered great attention, identifying the need for an updated, authoritative reference. Mushrooms: Cultivation, Nutritional Value, Medicinal Effect, and Environmental Impact, Second Edition presents the latest cultivation and biotechnological advances that contribute to the modernization of mushroom farming and the mushroom industry. It describes the individual steps of the complex mushroom cultivation process, along with comprehensive coverage of mushroom breeding, efficient cultivation practices, nutritional value, medicinal utility, and environmental impact. Maintaining the format, organization, and focus of the previous edition, this thoroughly revised edition includes the most recent research findings and many new references. It features new chapters on medicinal mushrooms and the effects of pests and diseases on mushroom cultivation. There are also updated chapters on specific edible mushrooms, and an expanded chapter on technology and mushrooms. Rather than providing an encyclopedic review, this book emphasizes worldwide trends and developments in mushroom biology from an international perspective. It takes an interdisciplinary approach that will appeal to industrial and medical mycologists, mushroom growers, botanists, plant pathologists, and professionals and scientists in related fields. This book illustrates that mushroom cultivation has and will continue to have a positive global impact on long-term food nutrition, health care, environmental conservation and regeneration, and economic and social change.
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Cells responsible for the natural killer (NK) effect in the human blood can be collected in the low-density lymphocyte subset and the majority of them express CR3. In addition to the iC3b binding site the CR3 molecules possess an epitope which binds beta-glucan. Ligands of this site can deliver activation signals to CR3-carrying monocytes and neutrophils. We found that the function of NK cells was also potentiated by preincubation with beta-glucan. The treatment increased the proportion of target-binding lymphocytes and of the damaged target cells in the conjugates. The monoclonal antibody OKM-1, directed to the beta-glucan-binding site of CR3, abrogated this effect. Another CR3-reactive monoclonal antibody, M522, known to activate monocytes and neutrophils, enhanced the NK function.
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In order to ascertain a correlation between infiltration of Langerhans cells (LCs) or T-cells in tumor tissues and the intratumoral administration of a biological response modifier, Sizofiran (SPG) was analyzed in cancer of the uterine cervix. Cancer specimens of 45 patients with stage II–III invasive cervical cancers were analyzed. SPG was administered to the cervical tumor at high and low concentrations (Strong SPG and weak SPG) as well as by intramuscular injection twice a week. LC and T-cell infiltrations to tumor tissues of the uterine cervix were studied immunohistochemically and electron microscopically. Of 10 patients with systemic but no local immunization, 1 (10.0%) showed an increase in LC infiltration and 2 (20.0%) showed a decrease. Of 15 patients with strong SPG immunization, 2 (13%) showed an increase and 5 (33%) showed a decrease. In contrast, of 20 patients with weak SPG immunization, the incidence of increase in LC infiltration was 55% (11 patients), significantly greater than the above-mentioned groups and none showed a decrease. Of the 20 patients with weak SPG administration, 3 (15%) showed T-cell infiltration before SPG administration, and 12 (60%) showed an increase in T-cell infiltration after SPG was given. Up on electron microscopy, Birbeck granules in the cytoplasm of LC significantly increased after SPG immunization, indicating activation of LC. In conclusion, the present study suggested that the LC and T-cell infiltrations in cancer tissues were augmented by intratumoral SPG administration at a certain concentration. Intratumoral administration of SPG may be applied to improve the prognosis after multidisciplinary treatment of advanced cervical cancer.
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(1→3)-β-d-Glucans that have β-d-glucopyranosyl units attached by (1→6) linkages as single unit branches enhance the immune system systemically. This enhancement results in antitumor, antibacterial, antiviral, anticoagulatory and wound healing activities. The (1→3)-β-d-glucan backbone is essential. The most active polymers have degrees of branching (DB) between 0.20 and 0.33. Data suggest both that triple helical structures formed from high molecular weight polymers are possibly important for immunopotentiating activity and that activity is independent of any specific ordered structure. Other data indicate that it is the distribution of the branch units along the backbone chain that is responsible for activity. There are data that indicate both that β-d-glucopyranosyl units are required for immunopotentiating activity and that the specific nature of the substituent is unimportant. There are also data that indicate both that the more water-soluble polymers are more active (up to a certain degree of substitution (DS) or DB) and that some insoluble aggregates are more stimulatory than the soluble polymers. The best conclusion at this time is that the immunopotentiating activity of (1→3)-β-d-glucans depends on a helical conformation and on the presence of hydrophilic groups located on the outside surface of the helix. Immunopotentiation effected by binding of a (1→3)-β-glucan molecule or particle probably includes activation of cytotoxic macrophages, helper T cells, and NK cells, promotion of T cell differentiation, and activation of the alternative complement pathway.