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Medicinal mushrooms as an attractive new source of natural compounds for future cancer therapy

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Medicinal mushrooms have been used throughout the history of mankind for treatment of various diseases including cancer. Nowadays they have been intensively studied in order to reveal the chemical nature and mechanisms of action of their biomedical capacity. Targeted treatment of cancer, non-harmful for healthy tissues, has become a desired goal in recent decades and compounds of fungal origin provide a vast reservoir of potential innovational drugs. Here, on example of four mushrooms common for use in Asian and Far Eastern folk medicine we demonstrate the complex and multilevel nature of their anticancer potential, basing upon different groups of compounds that can simultaneously target diverse biological processes relevant for cancer treatment, focusing on targeted approaches specific to malignant tissues. We show that some aspects of fungotherapy of tumors are studied relatively well, while others are still waiting to be fully unraveled. We also pay attention to the cancer types that are especially susceptible to the fungal treatments.
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Medicinal mushrooms as an attractive new source of natural
compounds for future cancer therapy
Artem Blagodatski1,2,*, Margarita Yatsunskaya1,*, Valeriia Mikhailova1, Vladlena
Tiasto1, Alexander Kagansky1 and Vladimir L. Katanaev1,2
1Centre for Genomic and Regenerative Medicine, School of Biomedicine, Far Eastern Federal University, Vladivostok, 690922,
Russian Federation
2Department of Pharmacology and Toxicology, University of Lausanne, Rue du Bugnon, 1011, Lausanne, Switzerland
*These authors have contributed equally to this work
Correspondence to: Alexander Kagansky, email: kagasha@yahoo.com
Vladimir L. Katanaev, email: vladimir.katanaev@unil.ch
Keywords: cancer; fungotherapy; medicinal mushrooms; targeted treatment; biomedicine
Received: April 11, 2018 Accepted: June 04, 2018 Published:
Copyright: Blagodatski et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License
3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and
source are credited.
ABSTRACT
Medicinal mushrooms have been used throughout the history of mankind for
treatment of various diseases including cancer. Nowadays they have been intensively
studied in order to reveal the chemical nature and mechanisms of action of their
biomedical capacity. Targeted treatment of cancer, non-harmful for healthy tissues,
has become a desired goal in recent decades and compounds of fungal origin provide
a vast reservoir of potential innovational drugs. Here, on example of four mushrooms
common for use in Asian and Far Eastern folk medicine we demonstrate the complex
and multilevel nature of their anticancer potential, basing upon different groups of
compounds that can simultaneously target diverse biological processes relevant for
cancer treatment, focusing on targeted approaches specific to malignant tissues. We
show that some aspects of fungotherapy of tumors are studied relatively well, while
others are still waiting to be fully unraveled. We also pay attention to the cancer types
that are especially susceptible to the fungal treatments.
INTRODUCTION
Nature has since long been an important source of
inspiration for the medicine. Throughout evolution, nature
produces a vast diversity of biologically active substances,
which possess enormous therapeutic potential, amongst
other things regarding the treatment of cancers. Natural
products have already yielded a series of compounds
widely used in anticancer chemotherapy, whilst application
of such products in folk and traditional medicine has
always been an important clue pointing to potential new
sources of compounds with therapeutic potential. Well-
known examples include camptothecin derived from the
bark and stem of the tree Camptotheca acuminata used in
Chinese traditional medicine [1], vinca alcaloids derived
from Madagascan periwinkle [2] or taxanes derived from
the Pacific Yew [3]. Nevertheless, such “first-generation”
natural chemotherapeutic agents are directed mostly
against housekeeping processes (such as DNA replication
or microtubule polymerization and stabilization), which
are more active against fast proliferating cancer cells, but
are in no way cancer-specific. This results in a variety
of harmful side effects in the conventional anticancer
chemotherapy, up to eventual patient’s death due to
overdose. More up-to-date approaches to cancer treatment
involve targeted therapies specific to the hallmarks of
cancer and harmless or of low harm to the healthy tissues
[4]. Search for compounds able to selectively act on cancer
cells or on tumorigenic processes is therefore a problem of
the highest priority in the field. Thus, it is a task of great
importance to “mine the treasury” of natural products for
such compounds in order to expand the arsenal of modern
oncology with a variety of highly specific tools.
www.oncotarget.com Oncotarget, Advance Publications 2018
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Cancer fungotherapy is a promising scientific field,
which deals with antitumor substances derived from
mushrooms. It has been an integral part of the world
traditional medicine since the antiquity [5].
The concept of fungal treatment officially appeared
in Traditional Chinese Medicine and can be dated back
to several thousand years ago [6] The ancient Chinese
pharmacopoeia included hundreds of herbal and fungal
species - the latter were considered to be the most effective
natural remedies for various types of tumors [6]. In other
countries of East and Southeast Asia, mushrooms were
also highly valued and rated as “beneficial to health” for
centuries. Plant and fungal products were also widespread
in Russia, representing the main medicinal resources until
the 18th century [7].
In the middle of the 20th century, some of the
earliest scientific research was performed on Boletus
edulis in order to study the antitumor activity of edible
and medicinal mushrooms [8].
Over the past 60 years, the rate of studies focusing
on fungi increased exponentially, but in many areas of
research mushrooms as potential source for beneficial
products are still ignored. For instance, 90% of fungal
species were never analyzed with respect to their antibiotic
and antitumor activity. Moreover, a large part of cancer-
related investigations done on fungi deals merely with
characterization of unspecific cytotoxic or cytostatic
effects on cancer cells (such effects would be harmful
for healthy cells as well), rather than with modulation of
specific oncogenic signaling pathways, which could be
targets for modern, highly specific anticancer therapies.
Importantly, a tumor has many “weak spots” and can be
targeted at different levels, such as tumor-specific pro-
proliferation signaling, regulation of apoptosis, cancer-
specific metabolism, angiogenesis, metastasis and,
last but not least, modulation of the immune system.
The peculiarity of medicinal mushrooms is that, being
producers of hundreds of compounds, they can affect
multiple cancer-related processes in synergistic ways
when used as a treatment. Thus, not only studies of certain
fungal-derived compounds are important, but also research
on complex anticancer effects caused by the combinations
of molecules in their extracts is of a high interest.
In this review, we intend to analyze the recent
knowledge, potential to cover the abovementioned
processes on the example of four Basidiomycota
mushrooms: Fomitopsis pinicola, Hericium erinaceus,
Trametes versicolor and Inonotus obliquus. The fields of
cancer fungotherapy and of search for novel antitumor
agents are by far not limited to these species; however,
these four can serve as typical representatives of
widespread medicinal mushrooms used both in traditional
medicine and in modern biomedical research. They belong
to three different orders, and are a rich source of bioactive
compounds such as polyphenols, polysaccharides,
glucans, terpenoids, steroids, cerebrosides and proteins,
which can be used for treatment of various cancers (Table
1). We chose these representatives to convexly illustrate
the therapeutic potential of the fungi and fungal-derived
products in relation to cancer and to inspire further
interdisciplinary work at the junction of oncology and
mycology, which should result in future discoveries of
novel low-toxic drugs with highly specific antitumor
activities.
Fomitopsis pinicola
Fomitopsis pinicola, class Agaricomycetes, order
Polyporales, family Fomitopsidaceae (common name Red
Belted Conk) (Figure 1), is a brown rot fungus, a member
of Basidiomycota. It is saprotrophic on the dead wood of
coniferous and broad-leaved trees, which are common
throughout the temperate Northern Hemisphere. [9].
F. pinicola fruiting bodies, which are considered to
be nontoxic mushrooms in Europe [10], have been used in
Korean folk medicine as hemostatic and anti-inflammation
agents [10] [11]. F. pinicola is known to contain a variety
of primary metabolites (such as polysaccharides) and
secondary metabolites (such as triterpenes, esters,
lactones and steroids) [12] [13]. Extracts and isolated
compounds from F. pinicola have demonstrated various
biological activities, including antioxidant [14] [15] [16],
antimicrobial [10], anti-inflammatory [17], and cytotoxic
[18] [19]. Regarding the antitumor potential of F. pinicola,
there is not much data present, but a few existing studies
motivate to expand the research in this direction. Indeed, a
nonspecific cytotoxic activity on human cancer cells such
as HeLa and hepatocarcinoma lines SNU 185 and SNU
354 has been shown for the methanol but not for water
extracts of F. pinicola [16].
Recently, more studies have been performed on F.
pinicola extracts in a search for more specific anticancer
activity. Chlorophorm extracts of the mushroom have
demonstrated cytotoxicity, which was almost twice more
specific to colorectal cancer cells (SW-480) than to control
HEK293 cells. The cytotoxic effect took place through
the ROS-mediated apoptotic mechanism. Moreover, the
extracts were able to inhibit migration of the SW-480
cells in scratch wound and transwell assays by means of
downregulation of matrix metalloproteinases [20]. The
authors claim that one (but not the only) of the acting
compounds of the mushroom is ergosterol, for it was
one of the major components of the extracts and could
produce similar, although slighter effects on SW-480
cells [20]. Another study has revealed the potential of
F. pinicola ethanol extracts not only to induce apoptosis
in various human and murine cancer cell lines, but also
to significantly inhibit xenograft sarcoma-derived tumor
growth in mice, along with prolongation of their survival
time and absence of severe side effects, when given as a
food supplement [21]. Interestingly, combined treatment
of mice with the extract and a common chemotherapeutic
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Table 1: The metabolites found in medicinal mushrooms and their therapeutic potential against cancer
Species Compound/derivative Targets/mechanisms of
action
Cancer types
affected
Experimental
models References
Fomitopsis
pinicola Methanol extract Cytotoxicity
Hepatocarcinoma,
cervical cancer Cell lines 16
Chlorophorm extract ROS-mediated apoptosis Colorectal cancer Cell lines 20
Metalloproteinase-
mediated migration
inhibition
Colorectal cancer Cell lines 20
Ergosterol ROS-mediated apoptosis Colorectal cancer Cell lines 20
Ethanol extract Tumor growth arrest Sarcoma
Mouse
xenograft
tumors
21
Hericium
erinaceus Ethanol extract Tumor growth arrest Gastric, liver,
colon cancer
Cell lines,
Mouse
xenograft
tumors
29
Water extract
Metalloproteinase-
mediated migration
inhibition, suppression
of ERK and JNK kinase
activation
Colon carcinoma
Mouse
xenograft
tumors
30
NK cells and
macrophages
stimulation, arrest of
angiogenesis
Colon carcinoma
Mouse
xenograft
tumors
30
Apoptosis via
downregulation of
antiapoptotic proteins
Leukemia Cell lines 31
Polysaccharides Immunostimulation, - Mouse models 32-34
Erinacine A (ditherpenoid) ROS-mediated cell cycle
arrest
Gastrointestinal
cancer, colorectal
cancer
Cell lines,
Mouse
xenograft
tumors
35-37
Antiinvasive
Cerebroside E Angiogenesis blocker - HUVEC cell
line 38
HEP3 protein Immunostimulation via
gut microbiota Adenocarcinoma
Mouse
xenograft
tumors
39
HEG-5 glycoprotein Proapoptotic stimulation Gastric cancer Cell lines 40
Ethanol extract Cytoprotective
Gastric ulcer
(carcinogenic
condition)
Rat model 42
1-(5-chloro-2-
hydroxyphenyl)-3-
methyl-1-butanone,2,5-
bis(methoxycarbonyl)
terephthalic acid
Helicobacter Pylori
growth inhibition
Gastric ulcer
(carcinogenic
condition)
In vitro
bacterial
growth models
43
Inonotus
obliquus Water extracts Cytotoxic/cytostatic Colon cancer,
liver cancer Cell lines 52-54
(continued )
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agent cisplatin gave a synergistic effect on slowing down
the tumor growth. Taken together, these findings provide a
stronger evidence that apart from the unspecific cytotoxic
compounds, F. pinicola contains substances possessing
specific anti-oncogenic potential, probably acting through
induction of apoptosis. Regarding the fact that F. pinicola
is known as an anticancer agent in the Chinese folk
medicine, we can conclude that this mushroom is of a
Species Compound/derivative Targets/mechanisms of
action
Cancer types
affected
Experimental
models References
Tumor growth inhibition Melanoma
Mouse
xenograft
tumors
55
Sarcoma 56
Inonotodiol and
inonotsuoxides ( lanostan-
type triterpenoids)
Tumor growth inhibition Skin cancer,
leukemia
Mouse
xenograft
tumors
48,57,58
Polyphenoles Topoisomerase II
inhibition (growth arrest) Colon carcinoma Cell lines 59
3,4-dihydroxybenzalacetone
NF-κB inhibition-
mediated apoptosis,
suppression of invasion
Gastric, liver,
colon cancer Cell lines 60
Polysaccharides Tumor growth inhibition
via immunostimulation
Colorectal cancer,
gastric cancer
Mouse
xenograft
tumors
47, 61-63
Migration inhibition,
anti-metastatic activities Lung carcinoma Cell lines 64,65
Ergosterol peroxide Inhibition of Wnt
signaling Colorectal cancer
Cell lines,
Mouse
xenograft
tumors
66
Inotodiol Breast cancer.
lung cancer
Cell lines
Rat model 68,69
Trametes
versicolor Water-ethanol extract Cytotoxic/
antiproliferative
Breast cancer,
cervical cancer,
B-lymphoma,
hormone-
dependent liver
cancer
Cell lines 72,73
Ethanol extract Cytotoxic/
antiproliferative Prostate cancer Cell lines 74
Glucans Tumor growth inhibition Sarcoma
Mouse
xenograft
tumors
75
β-glucan-based
polysaccharopeptide
fraction (PSP)
Tumor growth inhibition
via immunostimulation
Breast cancer,
gastrointestinal
cancer, lung
cancer
Mouse
xenograft
tumors, clinical
trials
76-81
Polysaccharide fraction
known as Krestin (PSK) 76, 82-91
YZP protein Immunostimulation Pancreatic cancer
Cell lines,
Mouse
xenograft
tumors
70
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certain interest for modern drug discovery as a potential
source of novel anticancer compounds, which are yet to
be characterized. Although ergosterol has been pinpointed
as one of the candidates, the exact chemical nature of the
acting compounds is still elusive. Biomolecular profiling
of inedible mushrooms has revealed an unusually high
phenolic content in F. pinicola, when compared to the
others [15] and polyphenols are known to be bioactive
compounds with anti-oncogenic properties [22]. Thus,
detailed studies on polyphenoles of F. pinicola is a
promising task for biomedicine.
Hericium erinaceus
Hericium erinaceus, class Agaricomycetes, order
Russulales, family Hericiaceae, is an edible medicinal
mushroom (Figure 2). It is also known under the name
“Lion's mane” in English, “Yamabushitake” in Japan or “
Hóutóugū ” in China. [23].
The mushroom is considered a saprotroph or a
weak parasite. It is found on oak (Quercus) and beech
(Fagus) in Europe, North America, Japan, Russia, and
China. [24]. H. erinaceus has attracted special scientific
attention in recent four years, being intensively studied in
terms of its primary and secondary metabolites and their
possible medicinal use. It yielded a number of compounds
belonging to different classes with potential biological
activity, which were tested against multiple targets
[25] [26] [27]. Among the isolated compounds, certain
were characterized, such as erinacines derived from the
mycelium or hericenones derived from the fruiting bodies
[27]. A significant part of research has been focused on
neuroprotective properties of the mushroom, which are
now extensively described in many works [28]. Another
large area of possible therapeutic and anti-carcinogenic
application of H. erinaceus is its salutary influence on the
digestive organs, including stomach, liver, intestine and
colon. Water and ethanol extracts of the mushroom have
demonstrated growth inhibitory effects on gastric (NCI-
87), liver (HepG2 and Huh-7), and colon (HT-29) cancer
cell lines in the MTT proliferation assay, with the highest
efficacy against Huh-7 cells (IC50 of 0.8 mg/ml for the
dried extract). Although not comparing these results with
non-cancer cell lines of the respective tissues, the same
study describes efficient application of the extracts against
xenograft tumors formed by aforementioned cancer cell
Figure 1: The anticancer properties of Fomitopsis pinicola. Effects of different mushroom derivatives and their mechanisms of
actions on various models are depicted. Mouse and cell icons indicate results obtained on animal and cell models, respectively. ROS –
reactive oxygen species, MMP↓ – downregulation of matrix metalloproteinases.
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lines in SCID mice. The extracts, given orally, have
demonstrated a tumor suppressing activity similar to
that of 5-fluoruracil, a most widely used drug clinically
applied for the treatment of gastrointestinal cancers,
but demonstrated a much lower general toxicity than
5-fluoruracil [29]. Another study shows that water extracts
of H. erinaceus, given as a food supplement, possess an
anti-metastatic activity, strongly inhibiting the migration
of CT-26 murine colon carcinoma cells to lungs after
intravenous injection into BALB/c mice, reducing the
formation of tumor nodules in the lung by about 50%, and
preventing metastasis-caused increase in the lung weight.
The mechanism of action involves suppression of matrix
melalloproteinases 2 and 9, as well as suppression of ERK
and JNK kinase activation, also decreasing the general
tumor cell viability [30].
Further research on tumor suppressing activity of
the H. erinaceus extracts allowed to reveal the possible
spectrum of their action modes. Studies on CT-26 derived
human colon cancer xenograft tumors in mice have shown
a significant reduction in tumor growth after treatment by
H. erinaceus water extracts. It has been demonstrated that
the extracts stimulated the activities of natural killer cells
and macrophages on one hand and blocked angiogenesis
on the other [30]. All these activities could contribute to
reduction of the tumor growth, although the anticancer
properties of the complex extract may not be limited by
them. Another study by the same group has demonstrated
a pro-apoptotic effect of same water extracts on U937
human monocytic leukemia cells in comparison to normal
human and murine fibroblasts, as measured by flow
cytometry. The mechanism of action is supposed to be
down-regulation of anti-apoptotic proteins (Bcl-2, Bcl-
xL(S), XIAP, and cIAPs), but not up-regulation of pro-
apoptotic ones [31]. Further concerning the exploration of
the immunomodulatory potential of H. erinaceus, it can
be stated that polysaccharide fractions of the mushroom
ethanol extract and derivatives thereof are able to promote
dendritic cell maturation and dendritic cell-mediated
cytokine production and T-cell proliferation [32], as
well as to activate macrophages and increase TNFα
production [33]. Stimulatory effects on intestinal immune
system, manifested mainly through increase of surface
IgA expression and natural killer cell activation, have
also been reported in mouse in vivo experiments, when
the polysaccharide fraction of H. erinaceus was given as
a food supplement [34]. Although these investigations
give no clue upon the exact structural and chemical
properties of the active polysaccharides, the idea of their
immunomodulatory input into the anti-carcinogenic
potential of H. erinaceus is very attractive.
Efforts to study anticancer effects of individual
compounds isolated from H. erinaceus have produced
impressive results. Cyanthine diterpenoid Erinacine A,
a mycelial derivative of H. erinaceus, has demonstrated
growth-inhibitory activities against different cancer cell
lines and tumors related to the digestive tract. It was able
to arrest the cell cycle through ROS-mediated activation
of the oxidative stress response, initiating potentiation
of the JNK1/2 MAPKs, p70S6K and mTOR pathways
in human colorectal adenocarcinoma cell line DLD-1.
It also showed significant proliferation decrease of the
Figure 2: The anticancer properties of Hericium erinaceus. Effects of different mushroom derivatives and their mechanisms of
actions in various models are depicted. Mouse and cell icons indicate results obtained on animal and cell models, respectively. Arrows up and
down reflect up- or down-regulation of respective proteins or pathways. ROS – reactive oxygen species, MMP - matrix metalloproteinases,
DC – dendritic cells, MP – macrophages, TC – T-cells, NK – natural killers. Other proteins/pathways are mentioned under their standard
names.
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DLD-1 and other colorectal cancer cell line HCT-116 in
comparison to the normal human colonic epithelial cells
when analyzed by the MTT assay. Finally, Erinacine A has
demonstrated an in vivo inhibition of DLD-1 xenograft
tumor growth in nude mice [35]. The anticancer activity
of Erinacine A mediated by ROS accumulation has also
been confirmed by comparative proteomic assays in
human gastric cancer cell lines MKN28 and TSGH9201
[36]. Further studies have also shed light on anti-invasive
properties of Erinacin A, which it demonstrated on DLD-
1 and HCT-116 colorectal cancer cells in the Boyden
chamber and scratch wound healing assays. Proteomic
studies have revealed the actin-binding proteins cofilin-1
and profilin-1 as downstream actors activated by the
Erinacine A-induced ROS response and mediating the
anti-invasive effect [37]. Another class of compounds
common for fungi are cerebrosides, and here cerebroside E
isolated from H. erinaceus has shown an ability to inhibit
(although slightly) the tube formation in the HUVEC cell
culture, thus being a potential angiogenesis blocker. This
compound also revealed antitoxic properties, reducing the
damage of LLC-PK1 kidney cells after cisplatin treatment
in culture – properties that may suggest it for the use in
complex cancer chemotherapies [38].
Interestingly, H. erinaceus is not merely a source
of low molecular weight biologically active compounds,
but also of some proteins that possess potential
tumor-suppressive activities. Indeed, a Hericium-
derived protein HEP3, which demonstrated a complex
immunomodulatory impact in mice, has also been able to
strongly reduce growth of CC531 cell xenograft tumors
after intraperitoneal injection. The immunomodulatory
effect was induced through stimulation of the gut
microbiota with the protein and involved activation of the
proliferation and differentiation of T-cells and stimulation
of the intestinal antigen-presenting cells [39]. Another
example of bioactive protein from the same mushroom is
a glycoprotein HEG-5 that was able to induce apoptosis
in a gastric cancer cell line SGC-7901, stimulating the
expression of pro-apoptotic factors such as p53, Bax,
Caspase 8 and Caspase 3 [40].
Another possible, though indirect, activity of
H. erinaceus, which can be relevant for the gastric
cancer is the ability of the fungal extracts to remediate
gastrointestinal ulcers which, on their turn, can be
classified as carcinogenic conditions. H. erinaceus has
been used to treat gastritis and gastroduodenic ulcer
in the Chinese folk medicine [41]. Ethanol extracts of
H. erinaceus have shown a cytoprotective effect after
treatment of alcohol-induced gastric ulcers in rats [42].
H. erinaceus is also able to inhibit growth of Helicobacter
pylori, the bacterium known to be the causative agent
for gastritis and ulcer. Analyses of petroleum ether
extracts of the mushroom have been performed, showing
ability of the extracts to suppress the growth of six
Helicobacter pylori strains in the microdilution assay
and in the disk diffusion assay in vitro. Separation of
the extracts yielded two active compounds, namely the
1 - ( 5 - chloro - 2 - hydroxyphenyl) – 3 – methy l- 1 -
butanone and the 2,5-bis(methoxycarbonyl)terephthalic
acid, which were responsible for the inhibitory activity
[43]. A polysaccharide composed of glucose, mannose,
and galactose isolated from the cultured mycelia of H.
erinaceus [44] was able to show antioxidant properties on
gastric mucosa cell line GES-1 after hydrogen peroxide
treatment, which makes this polysaccharide a good
candidate for one of components responsible for the
mushroom's gastroprotective effect [45].
Regarding the overall anticancer potential of
Hericium erinaceus, it can be stated that this medicinal
mushroom possesses a complex of active compounds,
which are able to block tumorigenesis at different stages
and by different mechanisms; most of them are confirmed
by both cell culture and xenograft experiments. It has
been demonstrated that H. erinaceus extracts or fractions/
components thereof exhibit: (i) immunostimulatory
activities, (ii) anti-metastatic activities through inhibition
of matrix metalloproteinases, (iii) gastro- and intestine-
protective activities, (iv) antioxidant potential, (v) pro-
apoptotic activities, (vi) inhibition of angiogenesis.
This spectrum of anticancer properties is provided by
different compounds: polysaccharides, lipids, terpenoids
(including unique erinacines), and even proteins. Thus,
two possible strategies of application of H. erinaceus to
cancer treatment are possible: studies on the complex
action of the extracts on patients with their further use
as cancer-preventive food supplements, and the detailed
investigation of compounds isolated from the mushroom
and their mechanisms of action for using them in targeted,
personalized anticancer therapy of the future. Up to date,
most of the cancer-related research of the mushroom has
focused on (though not limited by) gastrointestinal tumors.
Many preclinical trials on tumor-bearing mice indicate
H. erinaceus as a promising candidate for therapeutic
use in this field. Nevertheless, up to date no clinical
trials on the mushroom or compounds thereof exist,
moreover, many active compounds are still unidentified,
and many mechanisms of their action remain elusive.
Thus, Hericium erinaceus is a relatively well-studied
medicinal mushroom possessing a much larger therapeutic
potential for the future compared to its currently exploited
applications. Regarding the possibility to culture this
mushroom on industrial scale [46], it has a great chance to
become a part of modern natural products-based medicinal
biotechnology.
Inonotus obliquus
The mushroom Inonotus obliquus, class
Agaricomycetes, order Hymenochaetales, family
Hymenochaetaceae (also known as Chaga mushroom,
Figure 3) is a fungus that preferably grows as parasite
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on the trunks of living birch trees in the colder northern
climates [47].
I. obliquus has long been used in folk medicine for
cancer treatment in Russia, China, Korea and Japan [48]
[49] [50]. Water extracts of I. obliquus have demonstrated
cytotoxic and antimitotic activity on HeLa cells [51].
Extracts obtained from the mushroom by submerged
fermentation induced apoptosis in the human colorectal
carcinoma cell lines HCT-116 [52] and HT-29 [53].
Similar low-specific cytotoxic and/or cytostatic effects of
the Chaga extracts were reported on human colon cancer
cells [53] and liver cancer HepG2 cells [54] without,
however, elucidating the mechanisms of action. In vivo
experiments with I. obliquus extracts have provided data
on reduction of tumor growth by induction of apoptosis
in human melanoma B16-F10 cells-derived xenografts in
mice [55]. Growth of human Sarcoma-180 cells-derived
xenografts was as well suppressed by different sub-
fractions of the Chaga extract [56].
Regarding the anticancer potential of individual
compounds of I. obliquus, several groups can be
highlighted for this mushroom. Unique lanostan-type
triterpenoids inonotodiol and inonotsuoxides have revealed
anti-carcinogenic effects in vivo using the mouse skin [48]
[57] and human leukemia-derived mouse xenograft tumors
[58]. Low molecular weight polyphenolic compounds
demonstrated a topoisomerase II inhibiting activity leading
to growth reduction in cultured human colon HCT116
carcinoma cells, identifying these polyphenoles as
putative anticancer chemotherapeutic agents [59]. Another
Chaga-derived polyphenol, 3,4-dihydroxybenzalacetone,
inhibited the NF-κB activation and NF-κB-dependent
gene expression in a panel of human cancer cell lines
through blockade of IκBalpha (a subunit of NF-kappaB)
phosphorylation and inhibition of NF-κB activity followed
by suppression of synthesis of TNF-induced and NF-κB-
dependent proliferative, anti-apoptotic and pro-metastatic
gene products. These effects led to increase of TNF-
induced apoptosis and decrease of TNF-induced invasion
[60]. As Hericium erinaceus, the Chaga mushroom is
extremely rich in polysachharides, which may perform
immunomodulatory functions and inhibit tumorigenesis.
In vivo trials of different Chaga-derived polysaccharides
with different mouse xenograft tumor models have
demonstrated reduction of tumor growth along with
immunostimulatory effects [61] [62] [63]. Polysaccharides
from I. obliquus have also demonstrated anti-metastatic
activities and inhibition of migration in cancer cell culture
experiments, by blocking the expression and activity of
matrix metalloproteinases 2 and 9 via suppression of
MAPKs, PI3K/AKT, and NF-κB signaling pathways
[64] [65]. It is also important to highlight that the Chaga
mushroom contains ergosterol peroxide that has been
reported to inhibit growth of several human colorectal
cancer cell lines and of colon tumors in a mouse model
through the mechanism of Wnt/β-catenin pathway
downregulation [66]. This is particularly important,
because over-activation of this pathway is a cause of many
cancer types, such as colon, liver and breast and, moreover,
is highly specific to cancer in adult patients being virtually
inactive in healthy tissues [67]. Nevertheless, it has to be
pinpointed that the most recent studies confirm the Wnt/β-
catenin-inhibitory properties of the Chaga mushroom but
indicate other major compound as the active one, namely
Figure 3: The anticancer properties of Inonotus obliquus. Effects of different mushroom derivatives and their mechanisms of
actions in various models are depicted. Mouse and cell icons indicate results obtained on animal and cell models, respectively. Arrows up and
down reflect up- or down-regulation of respective proteins or pathways. ROS – reactive oxygen species, MMP - matrix metalloproteinases,
TopoII – topoisomerase II. Other proteins/pathways are mentioned under their standard names.
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the inotodiol, which efficiently suppressed Wnt-dependent
breast cancer proliferation under diabetic conditions
in a rat model [68]. As ergosterol is also found in other
medicinal mushrooms including Fomitopsis pinicola
discussed above, it can be one of important components
of targeted cancer fungotherapy in general. Recent HPLC-
tandem mass-spectrometry study of Chaga mushrooms
derived from France, Canada and Ukraine suggests that
the Chaga of French origin is the most rich on betulin
and betulinic acid, whereas Canadian Chaga is more rich
on inotodiol [69]. Taken together, the Chaga mushroom
can be regarded as a very promising but somewhat
understudied species, because in spite of its broad use in
folk medicine and of promising activities of extracts and
certain compounds against cancer in vitro and in vivo, not
many exact mechanisms of action are determined and no
clinical trials on human patients have been performed.
Trametes versicolor
Trametes versicolor, class Agaricomycetes,
order Polyporales, family Polyporaceae (Figure 4), is a
medicinal mushroom also known as Coriolus versicolor or
Polyporus versicolor, “Yun-Zhi” in China, “Kawaratake”
in Japan, and “Turkey tail mushroom” in English. This
fungus has been used as a therapeutic agent worldwide
[70]. It grows on tree trunks throughout the world in many
diverse climates, including North America [71].
A solid body of data exists on T. versicolor
cytotoxic, cytostatic and pro-apoptotic actions on various
cancer cell lines. Water-ethanol extracts of the mushroom
caused the proliferation inhibition on three human breast
cancer cell lines (T-47D, ZR75-30 and MCF-7), human
cervical cancer cell line Bcap37, human B-cell lymphoma
(Raji), human promyelocytic leukemia (HL-60, NB-4),
and human liver cancer cell line 7703 [72] [73]. Such
results do not prove anticancer function per se, but
provide some clues and fit well within the context of
other, more detailed data. Other studies have shown anti-
proliferative effects of an aqueous extract of T. versicolor
on human breast cancer (4T1), prostate cancer (DU145),
and hepatocellular carcinoma (HCC), when compared to
rat normal intestinal epithelial cells (IEC-6), and African
green monkey normal kidney (Vero) cell lines using the
MTT assay. The results demonstrated that the T. versicolor
extract was able to inhibit proliferation of DU145 and 4T1
cell lines in a dose-dependent way. The extract however
did not exert any significant anti-proliferative effect on
HCC, IEC-6, and Vero cell lines (IC50>1000 μg/ml),
showing its selective cytotoxicity for certain types of
cancer and its safety for normal cell lines. Studies of the
T. versicolor ethanol extract effects on human prostate
cancer cell lines have demonstrated the selectivity towards
inhibition of growth of the androgen-responsible cell line
LNcAP, while producing slight or no effect on hormone-
independent lines PC-3, DU-145, and JCA-1 [74].
Separation of T. versicolor extracts has yielded
many fractions and compounds, exhibiting targeted
impact on cancer cells in vivo and in vitro. The most
remarkable among them is the polysaccharide fraction
which, along with some isolated carbohydrates and
proteoglycans, possessed complex immunomodulatory
potential similar to that of Hericium erinaceus and
relevant for the anticancer treatment. As a recent example,
a new glucan has been isolated from this mushroom by
hot water extraction and subsequent chromatographic
purification and has demonstrated an ability to
significantly inhibit the xenograft sarcoma growth in
mice [75]. Most clinically relevant representatives of T.
versicolor-derived polysaccharides are the β-glucan-
based polysaccharopeptide fraction (PSP) and the
polysaccharide fraction known as Krestin (PSK) [76].
Both have underwent excessive clinical and preclinical
studies as immunotherapeutic anticancer agents [77].
Immunotherapy employing PSP has already become
a routine clinical practice in Japan since 1977 and in
China since 1987. PSP activates cells of the immune
system, boosts production of cytokines and chemokines
such as TNFα, interleukins (IL-1β and IL-6), histamine,
and prostaglandin E, stimulates dendritic and T-cell
infiltration into tumors and reduces the harmful side
effects of chemotherapy [78]. Some studies have been
performed to reveal the mechanism of PSP interaction
with the immune system. Experiments on peripheral blood
mononuclear cells from breast cancer patients have shown
that PSP drives cytokine expression through activation of
the TLR4-TIRAP/MAL-MyD88 signaling pathway [79].
It has also been found out that PSP treatment leads to
increased proliferation of the peripheral blood monocytes,
but does not directly affect the proliferation of T, B, and
NK cells [80]. Nevertheless, orally given combination
of PSP with acaccia resin as an adjuvant has led to a
significant increase of a hapten-induced specific T-cell
dependent B-cell response in mice, suggesting a complex
mechanism of PSP action [81]. The T. versicolor-derived
polysaccharide Krestin is an even more widespread and
better-studied immunomodulator used for anticancer
treatment. It is able to activate different types of immune
cells. PSK has shown the ability to stimulate dendritic cells
through the TLR2 receptor in vitro and to inhibit breast
cancer growth in the mouse model with the antitumor
effect dependent on CD8+ T-cell and NK cells, but not
CD4+ T-cells. PSK did not inhibit tumor growth in TLR2-
/- demonstrating that it is a specific TLR2 agonist and
has potent antitumor effects via activation of both innate
and adaptive immunity [82] [83]. In another study, PSK
enhanced the effect of trastuzumab-mediated anti-breast
cancer therapy when given orally, activating the NK cells
both directly and via interleukin-12 [84]. PSK has also
been able to activate murine macrophages via the TLR4
pathway, inducing TNFα and IL-6 secretion by wild type
but not by TLR4-deficient peritoneal macrophages [85]. It
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as well potentiated docetaxel-induced tumor suppression
and antitumor immune response in an immunocompetent
murine model of human prostate cancer [86]. Recent
studies indicate that the TLR2 agonist in PSK is a lipid
component, which acts cooperatively with the protein-
bound β-glucan [87].
Interestingly, a protein YZP purified from
T.versicolor has demonstrated a related ability: specific
triggering of differentiation of CD1d
+
B cells into IL-10-
producing regulatory B-cells, which promote the anti-
inflammatory function [70]. It is also worth-mentioning
that PSK has been shown to downregulate the over-
activated Hedgehog signaling cascade under hypoxic
conditions and to suppress the malignant phenotype
in pancreatic cancer in vitro and in mouse models
[88]. This may be extremely important, for Hedgehog
upregulation is a well-known hallmark of many cancer
types and a desired therapeutic target [89]. Here we,
again, observe a complex and synergistic action of several
chemically diverse compounds from the same fungal
species. Nevertheless, results on clinical trials exist that
do not prove high therapeutic efficacy of PSK in human
patients. Indeed, in Japan, PSK has been used for adjuvant
immunotherapy against gastric cancer. Patients with stage
II/III gastric cancer who underwent a surgical resection
were included into a retrospective study. All patients
received oral fluorinated pyrimidine anti-metabolites with
or without PSK after the operation, and no significant
difference between the control and the PSK group in
relapse free survival was detected [90]. Such examples
reflect that not all data obtained in model systems are
applicable to real clinical practice, and cancer therapies
have to be chosen very carefully to yield the desired
effects. Successful applications of PSK in human patients
have been demonstrated when the polysaccharide was
applied to treat lung cancer. Different sets of data on
non-randomized and randomized controlled clinical trials
exist that show improvement of various survival measures
including median survival and 1-, 2-, and 5-year survival,
improvement of immune function and reduction of tumor-
associated symptoms [91]. In any case, larger and more
rigorous randomized controlled trials for PSK in lung
cancer patients have to be performed [91].
Alongside the lung cancer, T. versicolor-derived
products are clinically applicable for the treatment of
breast cancer [71]. Many studies and some clinical trials
exist that describe the effect of the mushroom in animal
models and human patients. Thus, a natural dietary
supplement BreastDefend, which contains extracts from
medicinal mushrooms including T. versicolor, inhibits
proliferation and metastasis formation by the MDA-
MB-231 invasive human triple-negative breast cancer
Figure 4: The anticancer properties of Trametes versicolor. Effects of different mushroom derivatives and their mechanisms of
actions in various models are depicted. Human, mouse and cell icons indicate results obtained in human patients, animal and cell models,
respectively. Arrows up and down reflect up- or down-regulation of respective proteins or pathways. PSP – polysaccharopeptide, PSK –
polysaccharide Krestin, HH – Hedgehog pathway, TLR2, TLR4 – Toll-like receptors 2 and 4. IL-10 – Interleukin 10.
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cells in culture and suppresses their growth and breast-to
lung cancer metastasis in a xenograft mouse model [92].
There are single-case reports [93] and Phase I clinical
trial results [86] confirming that T. versicolor-based
treatment may be used as a supplement to conventional
anti-breast cancer therapy and lead to improvements of
the immune status in immunocompromised breast cancer
patients following standard primary oncologic treatment.
The mushroom preparations are widely used in up-to-
date integrative oncology and prescribed to patients on a
regular basis [94].
In general, T. versicolor can be characterized as
a medicinal mushroom, which is most actively used
in modern medicine in terms of anticancer treatment
compared to the other species discussed in this review. It
is mostly used as an adjuvant for cancer immunotherapy,
with data on clinical trials available, and has led to
development of several commercial medicines, mostly
acting as activators of the immune cells by the mushroom
polysaccharide fractions through Toll-like receptors.
Nevertheless, data on selective growth inhibition of
certain cancer cell lines in culture, without any immune
cells involved, suggest that there may be other specific
mechanisms of action at play, besides the ones described
before.
CONCLUSION
The complex anticancer potential of medicinal
mushrooms may be embodied not only through
inhibition of certain cancer-specific processes or targeted
activation of tumor-specific apoptosis, but also through
indirect actions such as immunomodulation [95]. The
polysaccharide-mediated antitumor immunomodulatory
action seems to be rather common for many medicinal
mushrooms and gives a major input into the therapeutic
potential of at least three out of the four reviewed species,
which is probably determined by similar carbohydrate
composition and thus similar effects on the immune
system of different mushrooms. Extrapolating these data,
we can suppose that other, less studied, polysaccharide-
rich mushroom species could possess similar or even
superior immuno-stimulatory properties. Moreover, some
of additional biological activities can be used for cancer
prevention, diminishing the risk of tumorigenic conditions;
to such activities we can attribute antioxidant, antibacterial
and anti-inflammatory properties. That is why research
on whole fungal extracts (sometimes reaching to the
clinical trials) and even on extracts of complex mixtures
of different medicinal mushrooms [96] are the important
part of the given research field.
The four mushrooms reviewed in this article
illustrate different stages of natural product-derived
drug development. Each medicinal plant or fungus
undergoes multiple stages of extraction, fractionation
and purification of active compounds. At the same time
these extracts, fractions and compounds are tested against
different cancer models, from tumor-derived cell lines
to animal models and clinical trials. Another dimension
is studying the mechanisms-of-action and targets of
the natural products and their derivatives. Maximum
progress in all these trials brings us closer to a perfect
natural drug for targeted cancer therapy. The mushroom
discussed first in our review, Fomitopsis pinicola, is
closer to the initial stages of involvement into modern
cancer treatment: it is known to possess certain anticancer
activities, and a set of compounds were isolated, but
experiments on animal models and clinical trials are
lacking, as well as precise studies on the molecular
targets and signaling pathways affected by the fungus.
Inonotus obliquus is a better-studied mushroom: here
we have more data on mouse xenograft experiments
and more molecular targets, including the Wnt/β-catenin
pathway, a promising target for anticancer drugs of the
future, but the medical relevance is still to be improved
by clinical trials. Hericium erinaceus and especially
Trametes versicolor are much more advanced in terms
of medical applications due to their uncovered strong
and complex immunomodulatory potential provided by
rich polysaccharide and proteoglycan diversity. There are
numerous clinical trials confirming applicability of these
mushrooms and their extracts as components of modern
anticancer chemotherapy. But the complex modes of
action and molecular targets as well as exact structures
of the active molecules from these mushrooms still have
to be studied in more detail. In general, there has been
a strong progress in the field of medicinal mushroom
research in terms of anticancer drug development, but
this work continues and much more progress still awaits
us, especially in the fields of molecular targets of the
medicinal mushrooms and the complex synergistic
interplay of their different components.
ACKNOWLEDGMENTS
The work was supported by Ministry of Education
and Science of the Russian Federation (project #
6.7997.2017/8.9). The photographs of the mushrooms
were kindly provided by Eugenia M. Bulakh.
CONFLICTS OF INTEREST
The authors declare that there are no conflicts of
interest between them for this manuscript.
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... Furthermore, krestin, calcaelin, hispolone, ganocidin, lectin, illudin S, hericium erinaceus polysaccharides A and B (HPA and HPB), lentinan, 3 schizophyllan, psilocybin, laccase, and a wide range of active compounds in mushrooms have exhibited anticancer potential [15]. Mushroom extracts and mushroom bioactive compounds have also been reported for activities, such as anticancer, antioxidative, antibacterial, antiviral, anti-inflammatory and other effects [16][17][18][19][20]. Besides, edible mushrooms have been used in cancer treatment, as an adjunct to conventional treatment or as a means of combating the side effects of cancer treatment. ...
... However, 90% of mushroom species have never been studied for their antitumor effects. In addition, cancer-associated fungi studies have been performed that only involve the characterization of non-specific cytotoxic or cytostatic effects on cancer cells [11,16,22]. Therefore, compounds derived from mushrooms are of great interest for the development of anti-cancer drugs. ...
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Objective: The study aimed to evaluate the multiple target effect of phytochemicals of mushroom against breast cancer using molecular docking and dynamics approach. Material and Method: In this study, the binding affinity of forty mushroom phytochemicals with various breast cancer proteins such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), topoisomerase IIα and topoisomerase IIβ were investigated by docking study using the PyRx tool. The selected receptors are highly cancer influencing and they were selected based on literature. Further molecular dynamics studies were also carried out to confirm the stability and conformation of the naringin-protein complex. In-silico ADMET studies were also carried out to confirm the pharmacokinetic properties and toxicity of the mushroom phytochemicals. Result and Discussion: From the results obtained, colossolactone G, antcin-A, and formipinioside had higher affinity to EGFR than normal neratinib. Furthermore, fomitoside K, naringin and antcin-A were found to have higher binding affinity than neratinib with HER2. Besides, ergone, naringin, and ergosterol showed higher binding affinity than doxorubicin during interactions with topoisomerase IIα. On the other hand, antrocin, ergosterol peroxide and naringin demonstrated higher binding affinity against topoisomerase IIβ than doxorubicin. Further molecular dynamics studies were also carried out to confirm the stability and conformation of the naringin-protein complex which revealed the best binding score against all the four tested enzymes. Overall, this study suggests naringin as the best ligand and may have great potential in breast cancer protein inhibitors development. To demonstrate their therapeutic promise against breast cancer, more in vitro and in vivo research might be required.
... Hericium erinaceus (Bull.) Pers., known colloquially as Lion's Mane, Yamabushitake, or Hóutóugū, has long been used in traditional Chinese medicine (Blagodatski et al., 2018;Gong et al., 2020). The dried mushroom contains 7.03% of water, 57.0% of carbohydrates, 22.3% of protein, 3.5% of lipids, 3.3-7.8% of dietary fiber, and 7.1% of ash (Łysakowska et al., 2023). ...
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... [23]. However, the action mechanisms of mushroom compounds are not clear and require further investigation [24]. The research reported here aims to contribute to our understanding of the action mechanisms of a few selected species of mushrooms and help us identify antibacterial compounds in these mushrooms. ...
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Bacterial resistance to antibiotics and the number of patients infected by multi-drug-resistant bacteria have increased significantly over the past decade. This study follows a computational approach to identify potential antibacterial compounds from wild mushrooms. Twenty-six known compounds produced by wild mushrooms were docked to assess their affinity with drug targets of antibiotics such as penicillin-binding protein-1a (PBP1a), DNA gyrase, and isoleucyl-tRNA synthetase (ILERS). Docking scores were further validated by multiple receptor conformer (MRC)-based docking studies. Based on the MRC-based docking results, eight molecules were shortlisted for ADMET analysis. Molecular dynamics (MD) simulations were further performed to evaluate the conformational stability of the ligand-protein complexes. Binding energies were computed by the gmx_MMPBSA method. The data were obtained in terms of root-mean square deviation, and root-mean square fluctuation justified the stability of Austrocortilutein A, Austrocortirubin, and Confluentin in complex with several proteins under physiological conditions. Among these, Austrocortilutein A displayed better binding affinity with PBP1a and ILERS when compared with their respective reference ligands. This study is preliminary and aims to help drive the search for compounds that have the capacity to overcome the anti-microbial resistance of prevalent bacteria, using natural compounds produced by wild mushrooms. Further experimental validation is required to justify the clinical use of the studied compounds.
... This is why the studies also lead to demonstrating their synergistic effect in extracts from Fomitopsis betu lina mycelium and fruit bodies. A cumulation of the compounds pre-sent in the extract results in a combination of molecules that may have complex anti-cancer effects as well as anti-inflammatory and anti-oxidative properties [6,30]. In extracts obtained from Fomitopsis betulina, even compounds with a low biological activity can enter various interactions, resulting in a stronger therapeutic effect or causing a synergistic reaction of the body on the physiological level. ...
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... In our research we used the extracts of medicinal mushroom, and this was probably the reason for the demonstrably higher total antioxidant activity, polyphenol content and phenolic acid content after the addition of Maitake extract in the amount of 10% compared to control breads and crackers. Furthermore, it should be noted that medicinal mushrooms such as Shiitake and Maitake are also a source of other valuable substances such as polysaccharides (beta-glucans), terpenoids, steroids, cerebrosides and various proteins with biological potential (Blagodatski et al., 2018). Regular consumption of designed bakery products can contribute to the improvement of selected health indicators as was confirmed in a clinical study among consumers who consumed cereal selenized onion biscuits with bioactive complex of selenium in organic form, quercetin (onion), curcumin (curcuma) and catechins (green tea) during the monitored period (Maďarič et al., 2013). ...
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... [23]. However, the action mechanisms of mushroom compounds are not clear and require further investigation [24]. The research reported here aims to contribute to our understanding of the action mechanisms of a few selected species of mushrooms and help us identify antibacterial compounds in these mushrooms. ...
... Medicine in Western Europe and America practically does not use fungi. [2][3][4][5] The current interest in fungi as sources of BACs arises to the fact that their sedentary lifestyle, like the lifestyle of plants, forces them to develop a wide range of adaptation strategies at the biochemical level, namely, to develop active secondary metabolism using specific metabolic pathways, since fungi are heterotrophs. ...
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