Novel Medicinal Mushroom Blend Suppresses Growth and Invasiveness of Human Breast Cancer Cells
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1529-1536.qxd 20/10/2010 10:56 Ì ™ÂÏ›‰·1529 INTERNATIONAL JOURNAL OF ONCOLOGY 37: 1529-1536, 2010 Novel medicinal mushroom blend suppresses growth and invasiveness of human breast cancer cells JIAHUA JIANG1 and DANIEL SLIVA1,2,3 1Cancer Research Laboratory, Methodist Research Institute, 1800 N Capitol Ave, E504, Indianapolis, IN 46202; 2Department of Medicine, and 3Indiana University Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA Received July 29, 2010; Accepted September 17, 2010 DOI: 10.3892/ijo_00000806 Abstract. Mushrooms are an integral part of Traditional dietary supplements (1). Recent epidemiological studies from Chinese Medicine (TCM), and have been used for millennia to Asia demonstrated that mushroom intake protects against prevent or treat a variety of diseases. Currently mushrooms or cancer, specifically gastrointestinal (GI) cancer and breast their extracts are used globally in the form of dietary supple- cancer (2-4). The anticancer activities of mushrooms were ments. In the present study we have evaluated the anticancer mainly linked to the modulation of the immune system by effects of the dietary supplement, MycoPhyto® Complex (MC), branched polysaccharides (glucans), glycoproteins or peptide/ a novel medicinal mushroom blend which consists of a blend protein-bound polysaccharides (5,6). Moreover, mushrooms of mushroom mycelia from the species Agaricus blazei, contain minerals, vitamins (e.g., thiamin, riboflavin, ascorbic Cordyceps sinensis, Coriolus versicolor, Ganoderma lucidum, acid, and vitamin D), amino acids, and other organic com- Grifola frondosa and Polyporus umbellatus, and ß-1,3-glucan pounds (7). Some of these natural mushroom compounds isolated from the yeast, Saccharomyces cerevisiae. Here, we demonstrated specific activity against aberrantly activated show that MC demonstrates cytostatic effects through the signaling pathways in cancer cells and were able to modulate inhibition of cell proliferation and cell cycle arrest at the G2/M specific molecular targets in the cell function including cell phase of highly invasive human breast cancer cells MDA-MB- proliferation, cell survival and angiogenesis (8). 231. DNA-microarray analysis revealed that MC inhibits MycoPhyto Complex (MC) is a dietary supplement expression of cell cycle regulatory genes (ANAPC2, ANAPC2, consisting of a mixture of six varieties of mushroom mycelia, BIRC5, Cyclin B1, Cyclin H, CDC20, CDK2, CKS1B, Cullin 1, including Agaricus blazei, Cordyceps sinensis, Coriolus E2F1, KPNA2, PKMYT1 and TFDP1). Moreover, MC also versicolor, Ganoderma lucidum, Grifola frondosa and suppresses the metastatic behavior of MDA-MB-231 by the Polyporus umbellatus, and additional ß-1,3-glucan isolated inhibition of cell adhesion, cell migration and cell invasion. from the yeast, Saccharomyces cerevisiae. Interestingly, these The potency of MC to inhibit invasiveness of breast cancer specific mushrooms have been linked to different health cells is linked to the suppression of secretion of the urokinase promoting or disease preventing functions. plasminogen activator (uPA) from MDA-MB-231 cells. In Agaricus blazei Murrill, popularly known as ‘Cogumelo do conclusion, the MC dietary supplement could have potential Sol’ in Brazil, or ‘Himematsutake’ in Japan, was originally dis- therapeutic value in the treatment of invasive human breast covered 50 years ago in Brazil (9,10). A. blazei is traditionally cancer. believed to treat many common diseases like atherosclerosis, hepatitis, hyperlipidemia, diabetes, dermatitis and cancer (10). Introduction The polysaccharide phytocomplex was suggested to be respon- sible for the immunostimulant and anti-tumor properties of Edible and medicinal mushrooms can produce a variety of A. blazei, probably through an opsonizing biochemical pathway biologically active compounds and can be therefore described (10). In addition, recent studies demonstrated anticancer as a novel class of nutraceuticals which are widely used as activities of A. blazei through the induction of apoptosis by the activation of caspase-3 in prostate cancer cells (11) and inhi- bition of constitutively active NF-κB in leukemic cells (12). _________________________________________ Moreover, A. blazei demonstrated anti-metastatic effect through the inhibition of MMP-9 in melanoma cells (13). Correspondence to: Dr D. Sliva, Cancer Research Laboratory, Cordyceps sinensis is the parasitic fungus that colonizes Methodist Research Institute, 1800 N Capitol Ave, E504, Indianapolis, the larvae of moths (Lepidoptera), and is native to the high IN 46202, USA altitude (3500-5000 m) of Himalayas (14). Cordyceps has been E-mail: [email protected] a valued medicine in Traditional Chinese Medicine (TCM) for more than 2000 years, and has been used for the treatment Key words: MycoPhyto, breast cancer, cell cycle, invasiveness, uPA of multiple disorders including respiratory, renal, hepatic, cardiovascular, immunologic, and nervous system, glucose metabolism, different inflammatory conditions and cancer 1529-1536.qxd 20/10/2010 10:56 Ì ™ÂÏ›‰·1530 1530 JIANG and SLIVA: DIETARY SUPPLEMENT MYCOPHYTO COMPLEX AND INVASIVE BEHAVIORS (15). The anticancer activity of C. sinensis, was associated isolated from G. frondosa, was associated with the stimulation with the presence of cordycepin (3-deoxyadenosine) which of natural killer (NK) cells and activation of macrophages and demonstrated inhibition of cell proliferation (16,17), induction differentiation of T-cells (45-47). Mechanistically, D-Fraction of apoptosis (18,19), and invasiveness (20). Mechanistically, increased expression of TNF-· in NK cells and IL-12 release C. sinensis extracts induced apoptosis by the activation of from macrophages and dendritic cells (45,47). Nevertheless, caspase-3 in leukemia cells and through the death receptor- phase I/II trials with a polysaccharide extract from G. frondosa mediated extrinsic and mitochondria-mediated intrinsic caspase demonstrated depressed as well as enhanced immune functions pathways in lung cancer cells or by the inactivation of Akt in cancer patients (48). Interestingly, G. frondosa ameliorated kinase in breast cancer cells, respectively (21-23). colon inflammation and suppressed TNF-· expression in the Coriolus versicolor is an obligate aerobe that is commonly colon tissue in an animal model of the inflammatory bowel found year-round on logs, stumps, tree trunks, and branches. disease (49). The direct anticancer effect was demonstrated The fungus occurs throughout the wooded temperate zones on the gastric cancer cells by the induction of apoptosis via of Asia, Europe, and North America and may be the most caspase-3-dependent and independent pathways (50). common shelf fungus in the Northern Hemisphere (24). C. Polyporus umbellatus (Zhu Ling in Chinese) has been used versicolor contains biologically active, structurally different in TCM as a remedy for the urinary tract infection and as a protein-bound polysaccharide-K (PSK) and polysaccharo- diuretic, and for the treatment of hepatitis B (51-53). Anti- peptide (PSP), which were approved in Asia for immuno- cancer activities of P. umbellatus have been demonstrated in therapy or as biological response modifiers (BRMs) (24,25). animal studies (54-56) as well as in one clinical study with In addition to the immunomodulatory activity, extracts of bladder cancer patients in China (57). Although the biological C. versicolor demonstrated direct effects on a variety of cancer activity of P. umbellatus was associated with the presence of cells. Therefore, C. versicolor induced apoptosis of breast polysaccharides (58), the cytotoxic activity against leukemia cancer cells through p53 and Bcl-2 dependent and independent cells was demonstrated with isolated triterpenes (polyporus- mechanisms (26) suppressed cell proliferation, and induced terones) isolated from P. umbellatus (59). In addition, other apoptosis of leukemia cells by mechanisms including inhibition ergostane-type ecdysteroids named polyporoids demonstrated of transcription factor NF-κB and down-regulation of expres- anti-inflammatory activity in a TPA-induced inflammation in sion of COX-2 (27). Moreover, direct cytotoxic effect of PSK, mice (60). Nevertheless, the molecular mechanisms responsible through the cell cycle arrest at G0/G1 phase and induction of for the anticancer activity of P. umbellatus were not addressed apoptosis associated with the caspase-3 expression, was in these studies. Anticancer activity of yeast ß-glucans is reported in various tumor cell lines derived from leukemia, associated with priming of neutrophils, macrophages and NK melanomas, fibrosarcomas and cervix, lung, pancreas and cells for cytotoxicity against tumors (61). Moreover, cancer gastric cancers (28). immunotherapy was recently evaluated in the combination of Ganoderma lucidum (Ling Zhi, Reishi) is one of the yeast ß-glucans with anti-tumor antibodies (62). important Asian fungi that have been recognized in China, In the present study, we evaluated anti-proliferative and Korea and Japan more than 4000 years ago (29). The biological anti-invasive properties of a dietary supplement MC on highly activity of G. lucidum is usually associated with polysac- invasive human breast cancer cells. charides (mainly glucans and glycoproteins) and lanostane- type triterpenes (ganoderic acids, ganoderic alcohols and their Materials and methods derivatives) (30). The anticancer effects of G. lucidum have been attributed to the modulation of the immune system