A. as Complementary Therapy in Cancer
Cancer is a dangerous disease which is characterized by an abnormal and uncontrolled cell growth that is able to spread (metastasize) to many organs. Due to its characteristics, cancer often results in death. Another term for cancer is “malignant tumor”. There are two types of tumor: benign (non-cancerous tumors) and malignant (cancerous tumors). The differences between both types are the ability to spread to many organs. A malignant tumor is able to invade and metastasize to other organs.(1)
Until now conventional therapies against cancer, such as surgery, chemotherapy and radiotherapy, still reach low success rates in a large number of cancer types. At present the use of complementary therapy from isolated natural products is starting to receive gaining interest in cancer treatment. A well known natural product that is used as complementary therapy against cancer is Ganoderma lucidum (GL) with β-D-Glucan as its bioactive substance.
is a Ganoderma lucidum polysaccharide peptide (GLPP) extract from mycelia. Each capsule contains 250 mg of polysaccharide peptide, in which it has 200 mg β-D-Glucan (180 mg β-1,3/1,6-D-Glucan). β-D-Glucan is an immunomodulator that modulates immune cells activities, especially macrophages.
β-D-Glucan works on several human immune receptors such as Dectin-1 (the main receptor), Toll-like Receptor 2 and 6 (TLR-2 and -6), Scavenger Receptor, Complement Receptor 3 (CR3), and Lactosylceramide. It induces a group of immune cells such as macrophages, neutrophils, monocytes, Natural Killer (NK) cells and dendritic cells to modulate the innate and adaptive immune responses. β-D-Glucan is then absorbed by colon peyer patch, and later on phagocyted and degraded by macrophages. Macrophages that contain β-D-Glucan will circulate in the spleen and lymph nodes and release smaller fractions of β-D-Glucan particles to activate other immune cells via the binding of β-D-Glucan with CR-3. These immune cells later are recruited to tumor cell which are coated with antibody and destroy it. In bone marrow these macrophages will also release β-D-Glucan particles to activate bone marrow stem cells.(2-4)
Fig. 5. Mechanism of Action of β-D-Glucan (PsP) as an Immunomodulator
B. as Chemoradioprotector in Cancer Therapy
Chemotherapy is a standard therapy in cancer. Unfortunately, chemotherapy eliminates not only cancer cells but also normal cells especially ones that proliferate quickly, such as gastrointestinal tract epithelial, hair follicle, nail and skin cells. There are several reasons that make chemotherapy ineffective. Chemotherapy is often followed by immunosuppression and neutropenia, which trigger infection and metastasis, and multidrug resistance (MDR) phenomenon. MDR appears due to the high increase in the level of P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP), causing chemotherapy agents to pump out of cancer cells.(5) Until now, chemotherapy only reaches low efficacy rates, such as in leukemia and lung cancer.
In vitro study shows that GLPP inhibits leukemic cancer cell resistance to adriamycin (K562/ADM) and human small cell lung cancer (SCLC) resistance to etoposide and doxorubicin.(5,6)
Fig. 6. GLPP inhibits Multidrug Resistance in Cancer Treatment
Ganoderma lucidum Polysaccharide Peptide (GLPP) which contains β-D-Glucan inhibits hematotoxicity due to chemotherapy-induced myelosuppression, which presents as neutropenia, leucopenia and thrombocytopenia. A phase I/II clinical study of β-D-Glucan in the treatment of patients with advanced malignancies receiving chemotherapy showed that β-D-Glucan was able to improved hematopoiesis and reduce leucopenia and thrombocytopenia.(7,8)
Fig. 7. GLPP promotes Myelopoiesis
Another standard therapy in cancer is radiotherapy which uses x or γ-rays to destroy cancer cells. Unfortunately, radiotherapy also decreases thymus, spleen’s weight and lymphocyte counts. Radiation also affects bone marrow around radiated-organs and causes myelosuppression. In a in vivo study it was shown that GLPP was able to increase thymus weight and splenocyte proliferation of γ-irradiated mice.(9)
Due to the above mentioned beneficial effects of β-D-Glucan, is used as chemoradioprotector for cancer patients who receive chemo and/or radiotherapy.
C. as Complementary Therapy in Myocardial Ischemia
Myocardial ischemia occurs if oxygen and nutrients supply for cardiomyocytes supplied by coronary arteries is imbalanced with the cardiomyocyte demand. This imbalance is mainly caused by atherosclerotic plaque in the coronary artery circulation. Myocardial ischemia is also associated with inflammation and a cytokines cascade resulting in myocardial infarction and the subsequent development of heart failure (HF).(10)
Coronary Artery Bypass Grafting (CABG) is a standard surgical procedure to restore the blood flow into the heart. Two crucial points that comes to our attention about this process would be that there is a possibility that this procedure could be followed by inflammation and that there is a decrease in cardiomyocytes conractile capability, which is identified as “low cardiac output syndrome”, that affects 9% of the patiens who under go CABG.(11)
In ischemia or reperfusion conditions, cytokines activate the Nuclear Factor-kB (NF-kB) signaling pathway through Toll-like Receptor-4 (TLR-4) on the cardiomyocytes surface. As a result cardiomyocytes apoptosis occurs. β-D-Glucan with its cardioprotective effect on ischemia-reperfusion injury is able to bind with TLR-4 and shift the NF-kB signaling pathway towards the Phosphoinositide3-kinase (PI3K) signaling pathway resulting in cardiomyocytes survival. In a clinical study it was proved that pretreatment with oral β-D-Glucan for patient undergoing CABG resulted in cardioprotective effects as demonstrated by myocardial enzyme depletion in blood. (11,12)
In 2013, , in collaboration with Faculty of Medicine Brawijaya University (Malang- East Java, Indonesia), conducted a pre-clinical study of in in vivo model of atherosclerosis and type II Diabetes Mellitus. The result of this study demonstrates the ability of in inhibiting atherosclerosis progressivity through its mechanism of action as anti-inflammation and anti-oxidant. The anti-inflammatory activity of is confirmed by the reduction of Interleukin-6 (IL-6) and high sensitive-C Reactive Protein (hs-CRP) level in blood; whereas the anti-oxidant activity of PsP is confirmed by the reduction of Malondealdehyde (MDA) as end product of lipid peroxidation which causes oxidative stress to vascular cells. The anti-oxidant activity of PsP is also able to increase the level of antioxidant enzyme Superoxide Dismutase (SOD) in blood. The improvement of lipid profile is in the form of the reduction of Total Cholesterol (TC) and Low-density Lipoprotein (LDL), which also describes the enhancement of High-density Lipopropotein (HDL) in PsP treatment group. The reduction of foam cell formation in treatment group also supports the proof that PsP can be used to inhibit progressivity of atherosclerosis.(13,14). A detailed explanation about PsP’s preclinical study can be reviewed for your perusal at
In a study it was observed that macrophages in Peyer’s patch would phagocytized orally administrated β-D-Glucan to smaller fragments. These β-D-Glucan fragments were then transported and released in bone marrow where they could bind with Complement Receptor 3 (CR3) in the bone marrow stem cells. This binding stimulated complement activation that caused stem cells to proliferate, differentiate and recruit into injury site which expressed iC3b including injured cardiomyocytes.(15) β-D-Glucan in would bind with CR3 in bone marrow and cardiac stem cells, stimulate complement system activation and induce stem cells to proliferate, differentiate and recruit into injured cardiomyocytes to replaced them.
Fig. 9. β-D-Glucan Stimulates Stem Cell Proliferation, Differentiation and Recruitment to the Site of Injury
D. as a Complementary Therapy in Hepatitis B and C, Fibrosis and Cirrhosis
Viral Hepatitis B and C (HBV and HCV) generally proceeds to chronic hepatitis, fibrosis, cirrhosis and even liver cancer (hepatocellular carcinoma/HCC). In recent findings, the standard therapies for viral hepatitis infection are Interferon-α (IFN-α) and nucleoside analog (anti-viral), although the efficacy of both therapies are low. In addition, the long term use of analog nucleoside can exert resistance because the HBV and HCV are known to have high mutation rate.
The immune system plays an important role in HBV or HCV elimination which is mediated by cytotoxic T lymphocyte (CTL). The binding of β-D-Glucan with its receptor in immune cells, mainly in macrophages, results in cascade activation of cytokine secretion in other immune cells including CTL response to HBV and HCV.
In a clinical study it was shown that chronic hepatitis B patients who received GLPP for 3 months resulted in HBV DNA and HBeAg depletion in 25% patients. 6 months follow up resulted in HBsAg negative in 13% patients. This percentage was high (significant difference) compared to the group of control patients (not receiving GLPP). As an immunomodulator, Ganoderma lucidum antiviral activity works through the inhibition of: (16,17)
- viral hepatitis absorption and fusion with hepatocytes
- viral hepatitis endocytosis, integration and assembly in hepatocytes
- viral hepatitis release from hepatocytes
Viral hepatitis is not the only factor that causes chronic hepatitis. Other factors are alcohol, drug abuse, and also metabolic disease. Chronic hepatitis usually develops into abnormal accumulation of extracellular matrix (ECM) in the liver and becomes cirrhotic with poor prognosis result in HCC.
GLPP’s hepatoprotective properties are antioxidative and antifibrotic. As an antioxidant GLPP prevents hepatocytes damage through its free radical scavenger mechanism. With its antifibrotic activity GLPP inhibits hydroxyprolline synthesis (ECM component) through hepatic stellate cells (HSC) activated by proinflammation cytokine (TNF-α and IL-1β) in chronic inflammation. Due to the above properties, is used as complementary therapy in chronic hepatitis B and C, fibrosis, cirrhosis and HCC.(18)
E. as Complementary Therapy in Diabetic Foot Ulcer
Diabetic foot ulcer is a diabetic complication that is hard to overcome. Hyperglycemia causes endothelial abnormalities (microcirculation deficiency), neuropathy and wound cells (macrophages and fibroblasts) abnormalities resulting in wound healing delay.(19)
Depletion of endothelial Nitric Oxide Synthetase-derived Nitric Oxide (eNOS-derived NO) as a vasodilator, basement membrane thickening and reduction of capillary size are caused by microcirculatory deficiency. As a result leucocytes cannot reach wound area for inflammation process to clean the debris and prevent infection. (19)
Diabetic neuropathy usually affects sensory, motoric and autonomic nerves. This neuropathy causes the patient to be unaware of their initial wound until the wound becomes a severe ulcer.(19)
Macrophages and fibroblasts are very vital in the wound healing process. Diabetic hyperglycemia inhibits macrophages from secreting cytokines, such as Tumor Necrosis Factor-α (TNF-α), Interleukin-1β (IL-1β) and growth factors: Vascular Endothelial Growth Factor (VEGF), Platelet Derived Growth Factor (PDGF), basic Fibroblast Growth Factor (bFGF). These cytokines are necessary to activate angiogenesis and lymphangiogenesis during wound healing process. Synthesis of collagen by fibroblasts to increase tensile strength is impaired due to the hyperglycemia condition. (20)
Under the influence of the immune system wound healing processes are heavily depended on macrophages, fibroblasts, keratinocytes with cytokines, and growth factors. As a consequence agents or substances with immunomodulatory activity play a significant role in the reparative process. (21)
β-D-Glucan in is able to induce macrophages to secrete growth factor (VEGF) which is needed for angiogenesis and lymphangiogenesis in the wound healing process. β-D-Glucan is also able to stimulate fibroblasts to synthesize collagen. Systemic or oral β-D-Glucan administration enhances the wound healing process itself and stimulates macrophages infiltration to wound area, tissue granulation, collagen deposition, re-epithelization and tensile strength. Due to the properties of β-D-Glucanmentioned above, should be used as complementary therapy in diabetic foot ulcer.(22-24)
Fig. 10. The Effects of β-D-Glucan on Macrophage and Fibroblast in the Wound Healing Process