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Abstract
Ganoderma lucidum mushroom (also known as Ling Zhi in China, Mannetake /Reishi in Japan) has been
widely used for thousands of years to prevent and treat various diseases, such as heart disease, diabetes
mellitus, viral infection, and cancer. Polysaccharides from Ganoderma lucidum has been extensively
investigated for free radical scavenging activity. Both in vivo and in vitro studies suggest that G. lucidum
have anti-tumor effects, which mediated by its immunomodulatory, anti-angiogenesis, and cytotoxic
effects. Ganoderma lucidum polysaccharide peptide (GLPP) which extracted from Ganoderma lucidum
mycelium tissue culture, give the best quality of β-D-Glucans bioactive compounds. These biologically
active glucans interact with receptors on the surface of immune cells such as macrophage and natural
killer cell (NK cell) to induce immunomodulatory and tumoricidal effects. However, many studies still
need to answer those mechanisms.
Key words: Anti-tumor effects, β-Glucan, Ganoderma lucidum, GLPP, immunomodulatory activity
Correspondence: Dr. dr. Imam Rasjidi, SpOG (K) Onk, Department of Obstetry and Gynecology, Faculty of
Medicine, Pelita Harapan University, Tangerang, Indonesia, email: imam_rasjidi@yahoo.co.id
Received: 5th January 2015, Accepted: 17th February 2015, Published: 1 June 2015
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cells such as: Dectin-1, Complement via the Dectin-1 receptor and subsequently
Receptor 3 (CR3), Toll Like Receptor (TLR), transported to the spleen, lymph nodes, and
Scavenger Receptor and Lactosylceramide bone marrow. Within the bone marrow, the
Receptor.7 The β-D-Glucan binding site of macrophages degraded the large β-D-Glucans
CR3 has been mapped to a region of CD11b into smaller soluble β-D-Glucans fragments.
located C-terminal to the I-domain and its The small β-D-Glucans fragments were then
distinct metal ion-dependent adhesion site released by the macrophages and taken up by
for the many protein ligands of CR3 such as the circulating granulocytes, monocytes and
iC3b, ICAM-1 and fibrinogen. Some of them dendritic cells. Despite low systemic blood
have shown significant immuno-modulating levels (less than 0.5%), significant systemic
activities.4 In a study using a suckling rat immunomodulating effects in terms of
model for evaluation of the absorption and humoral and cellular immune responses were
tissues distribution of enterally administered demonstrated.7
radioactive labeled β-D-Glucans, it was
found that the majority of β-D-Glucans was Pharmacodynamic/Mechanism of Action of
detected in the stomach and duodenum 5 GLPP
minutes after the administration. This amount
rapidly decreased during first 30 minutes. 1. Immunomodulating Activity
Its transit through the proximal intestine GLPP are potent stimulators of murine
decreased with time with a simultaneous and human macrophages in vitro and in
increase in the ileum.7 vivo. Among the multiple polysaccharide,
The orally administered β-D-Glucans were active β-D-Glucans are responsible for the
taken up by macrophages in the Peyer patch immunomodulating effect. β-D-Glucans
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appear to act by binding to leucocyte surfaces of GLPP are extensive, including promoting
or serum-spesific proteins such as: Dectin-1, the function of APC, mononuclear phagocyte
Complement Receptor 3 (CR3), Toll Like system, humoral immunity, and cellular
Receptor (TLR), Scavenger Receptor and immunity.8 Lin ZB (2005) suggested that
Lactosylceramide Receptor, are leading GLPP potentiated the release of IFN-ɣ from
to activation of macrophages, lymphocyte human T cells. GLPP promoted the production
T-helper, NK-cells, and other effector cells. All of IL-2 in a dose-dependent manner and
of these increase the production of cytokines markedly enhanced the cytotoxicity of
by the activated effector cells, such as tumor cytotoxic T lymphocytes. Moreover, GLPP
necrosis factor-alpha (TNF-α), interleukins increased the production of IFN-ɣ mRNA
(IL), interferons (IFN), nitric oxide (NO) and expression in the T-lymphocytes. In addition,
antibodies.4,7 The immunomodulating effects treatment of dendritic cells with GLPP
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resulted in enhanced T cell-stimulatory cell line) in vitro and human umbilical cord
capacity and increased T cell secretion of vascular endothelial cell in vitro. The results
IFN-ɣ and IL-10.21 Taken together, these showed that GLPP could inhibit tumor cells
data demonstrate that GLPP can effectively growth in mice with dose dependency. Further
promote the activation and maturation of intermediate research by Cao and Lin (2006)
immature DC, activation of T lymphocytes, elucidated the possible mechanism of GLPP
suggesting that GLPP may possess a potential action as anti-tumor. GLPP could reduced
in regulating immune responses. B cell lymphoma-2 (Bcl-2) expression and
increased Bax expression in human umbilical
2. Anti-tumor Effects cord vascular endothelial cell.
Anti-tumor activity of GLPP had been GLPP fraction had also been reported to
investigated by several studies. A study held by inhibit the proliferation of human colorectal
Cao and Lin (2004) showed GLPP anti-tumor cancer cell SW 480 by inhibiting the synthesis
effects in sarcoma 180-bearing mice in vivo, of DNA and decreasing the formation of radical
tumor proliferation (human lung carcinoma DPPH (radical scavenging activities).11 The
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drugs from tumor cells. The reversal effect functions in 34 advanced stage cancer
of GLPP on MDR in K562/ADM cell line patients. For the inclusion criteria, Gao, et al
(K562 cell line that is resistant to adriamycin) choose the advanced stage cancer arising from
has been researched by Li, et al (2008). They various tissues with ECOG performances
showed that GLPP could reverse the sensitivity status of 0–2 and a projected life expectancy
of K562 cell line to adriamycin, GLPP could of ≥ 12 weeks. The patients also have adequate
downregulate the P-gp and MRP functional bone marrow function, renal function and
expression in the K562/ADM cells compared liver function and informed consent for
to the control group (without treatment with participation. The patients were treated with
GLPP). Furthermore, the effect of GLPP on 1800 mg, three times daily orally before meal
ADM accumulation in K562/ADM cells has for 12 weeks. Each capsule contained 600
been tested. The result showed that GLPP mg extract of Ganoderma lucidum, with 25%
increased the accumulation of adriamycin in (w/w) crude polysaccharides.
K562/ADM cell line compared to the control Treatment of GLPP for 12 weeks resulted
group (without treatment with GLPP).16 in a significant increase in the mean plasma
MDR also a major problem in small cell concentrations of IL-2, IL-6 and IFN-γ,
lung cancer (SCLC). One of the study tested whereas the levels of IL-1 and TNF-α were
the effects of Ganoderma lucidum mycelium significantly decreased. The inhibitory effects
on drug-sensitive (H69) and multi-drug of GLPP on TNF-α production may result in
resistant (VPA) human SCLC cells. Cells beneficial effects (e.g. improved life quality)
treated with the initial concentration (IC50) in advanced stage cancer patients. Increased
of cyotoxic Ganoderma lucidum mycelium TNF-α has been thought to contribute to cancer
and analyzed by flow cytometry-PI staining cachexia that is manifested by bodyweight
showed increased in S phase. When comparing loss, chronic nause, fatigue, insomnia and
untreated controls or SCLC cells treated profuse sweating. The mean absolute number
with extracts of non-cytotoxic Ganoderma of CD56+ cells was significantly increased
species, cells treated with extracts of cyotoxic after 12 weeks treatment of GLPP, whereas
Ganoderma lucidum mycelium responded the baseline levels, with the CD4:CD8 T
with an induction of apoptosis similar to cells cell ratios unchanged. In addition, GLPP
treated with the chemotherapeutics drugs treatment resulted in a significant increase
etoposide and doxorubicin. This study results in the mean NK activity compared to
showed that in both drug-sensitive and baseline (34.5±11.8% vs 26.6±8.3%).20
drug-resistant SCLC cells, pre-incubation Gao, et al also do a randomized, placebo
with active Ganoderma lucidum mycelium controlled, multicenter study of Ganoderma
extracts indeed significantly lowered the lucidum polysaccharide extract in 68 patients
IC50 dose of etoposide or doxorubicin.17 with advanced lung cancer. Patients were
randomized to be given Ganoderma lucidum
Clinical Study of GLPP polysaccharide (GLPP) (n=37) or placebo
(n=31) for 12 weeks. Treatment with GLPP
Ganoderma lucidum has been collected and gave stable disease (SD) in 13 (13/37, 35.1%)
used for hundreds of years in many countries. lung cancer patients at the 12 week evaluation
Some clinical study of GLPP on advanced point, which was significantly greater than
stage cancer had been held. Gao, et al (2003) that of control group (7/31, 22.6%). In 32
studied the effects of Ganoderma lucidum assessable cancer patients, treatment of GLPP
polysaccharide extract on the immune resulted in a significant increase (>10 scores)
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