Defining a Role of Amanita phalloides Toxins in Cancer: Research and Therapy

Abstract

Despite the progress of diagnostic and therapy, the cancer burden is still rising worldwide. The new chemotherapeutical toxicity to somatic cells and its tolerance to tumor cells illustrates the immediate demand through recent pharmaceutical products with less harmful impacts. The use of natural anticancer products, like α-amanitin toxins have reached the cancer field therapy since the separation of Amanita phalloides fungi was performed. Application of Amanita phalloides affects tumor cell activity. It is thought that Amanita phalloides dilutions are recommended for a patient suffering from various cancer types and have no severe side effects resulting from amanita therapy. This review aims to explain the use of the therapeutic potential of α-amanitin toxin against different cancer types.

Full text

Vol. 02, No. 01, pp. 07 – 12 (2021)
ISSN: 2708-1818
JOURNAL OF LIFE AND BIO-SCIENCES RESEARCH
www.jlbsr.org
7
doi: 10.38094/jlbsr20137
Defining a Role of Amanita phalloides Toxins in Cancer:
Research and Therapy
Noor T. Hamdan
Biology Department, College of Science, Mustansiriyah University, Baghdad, Iraq (noor.t.hamdan@uomustansiriyah.edu.iq)
Abstract
Despite the progress of diagnostic and therapy, the cancer burden is still rising worldwide. The new chemotherapeutical toxicity to somatic
cells and its tolerance to tumor cells illustrates the immediate demand through recent pharmaceutical products with less harmful impacts.
The use of natural anticancer products, like α-amanitin toxins have reached the cancer field therapy since the separation of Amanita
phalloides fungi was performed. Application of Amanita phalloides affects tumor cell activity. It is thought that Amanita phalloides
dilutions are recommended for a patient suffering from various cancer types and have no severe side effects resulting from amanita
therapy. This review aims to explain the use of the therapeutic potential of α-amanitin toxin against different cancer types.
Keywords: Amatoxins, Amanita phalloides, cancer therapy
Received: January 30th, 2021 / Accepted: March 10th, 2021 / Online: March 19th, 2021
I. INTRODUCTION
Cancer is considered as the world second leading cause of
death and the most difficult illness to handle (Paul et al.,
2013). Globally, despite the advancement of diagnosis and
treatment, the incidence of cancer is still increasing. The
World Health Organization reports that about 9.6 million new
cases of cancer accusing in 2018 are going to rise to 21.3
million by 2030 worldwide (Song et al., 2013).
Many cytotoxic therapies can stop the disease's progression
from the tumor, but they are mostly too harmful to normal
cells, leading healthy tissues to be in a critical situation
(Tripathy and Pradhan, 2013). This restricts their efficacy and
their use as chemical therapy and emphasizes the immediate
need to produce agents, which reduce adverse effects on
normal tissues. To overcome this necessity, the utilizing of
mushroom (i.e. α- amanitin) has approached the cancer field
and further isolation from amanitin fungi has been practiced
(Paul et al., 2013).
The Amanita genus includes approximately 900-1000 agarics
species, containing some of the world’s most toxic identified
mushrooms, and few well-recognized edible species (Berch
et al., 2017; Zhang et al., 2015). This genus Amanita accounts
for about 95% of the deaths induced by mushroom toxicity,
although the death cap comprising approximately 50% alone
(Beug et al., 2006; Moor- Smith et al., 2019).
The
lethal dose
of
amanita
toxin
is
0.1
mg/kg
of
body
weight
and so
acute
toxicity
of
amanita
toxin
at
5
to
7
mg
dose
will
occur
(Jander et al., 2000). The kidneys absorb the amanita
toxin, also its typically not observed until 48 hours after
absorption in the plasma (Garcia et al., 2015a). Therefore,
immediate clinical action is needed to prevent server
complications. Several case series demonstrated increased
survival relative to the historical survival level (Jander and
Bischoff, 2000).
The main active toxin found in these mushrooms named α-
amanitin (Rodrigues et al., 2020). Although there are many
edible mushrooms in this genus, mycologists dishearten
mushroom collectors choosing them for human use, rather
than knowledgeable experts. However, in some cultures,
Amanita is the main local edible species in the local growing
season (Diaz, 2018). The toxicity of lethal Amanita
mushrooms are distinguished by non-striated and non-
appendiculated pilei, attenuated lamellulae, constant annulus
presence, a base of bulbous stipe, and volva limbate and
basidiospores amyloid shape (Escudié et al., 2007; Cai et al.,
2016). Among them, the most deadly toxic mushroom species
identified today are Amanita phalloides (zert. Riede), the
death cap, resulting in 90-95% of all overall mushroom
toxicity deaths (Figure 1) (Santi et al., 2012; Garcia et al.,
2015b). Cholera-like signs accompanied by diarrhea, nausea
and vomiting starting 10-20

Hamdan / Journal of Life and Bio-sciences Research Vol. 02, No. 01, pp. 07 – 12 (2021)
8
h after ingestion, then hepatitis, renal failure and subsequent
death (Kieslichova et al.,2018; Horowitz and Moss, 2020).
The main death toxins in chosen Amanita species include
amino acids and cyclopeptides. In addition, isoxazoles are
considered as toxic substances, which cause hallucinogenic
symptoms present inside some Amanita genera (Zilker and
Faulstich, 2017; Yin et al., 2019). The toxic compounds in
Amanita phalloides are resistant to temperature, therefore not
influenced by cooking (Pulman et al., 2016; Loizides et al.,
2018).
A. phalloides mushroom toxicity is associated with two main
toxins: amatoxins and phallotoxins. Phallotoxins are less
toxic because they degraded quickly by heat and digestion.
Amatoxins are considerably more important substances that
induce clinical poisoning and have 10 to 20 times higher
toxicity than phallotoxins (May et al., 2008; Yilmaz et al.,
2015).
Figure 1. Amanita phalloides (a) amyloid spores and fruit body, (b)
spores and (c) on the left ripe mature mushroom and on the right ripe
young mushroom (Yilmaz et al., 2015).
Cell destructive therapies such as chemotherapy and utilizing
cellular apoptosis induction programs are not yet effective in
prolonging a patients life. This is attributed to the tumor cells'
resistance to several therapies, and their genetic failure to
cause apoptosis (Rodrigues et al., 2020). In the traditional
context, A. phalloides utilized to overcome the death risk. In
a molecular context, newly discovered of this extraction has
properties to suppress tumor cells formation.
There are limited information on α-amanitin therapy or a
combination of α-amanitin and chemical substances, for
example, recently Amanita phalloides were used for cancer
therapy after a German scientist, Isolde Riede, began
supporting cancer patients with a homeopathic formulation of
Amanita with remarkable success.
The first case study on cancer patients was reported in
German 2009 and was revealed a great change with breast
cancer patients after Amanita therapy (Riede, 2009).
Moreover, Technique using a monoclonal anti-EPCAM
antibody combined with α-amanitin as a cancer
immunotherapy. Moldenhauer et al., (2012) showed strong
growth inhibition impacts on the individual pancreatic cancer
without adverse effects at 0.1 mg/kg dose.
Another study published by Kume et al, (2016) about
combination therapy of α-amanitin (α-AMA) and cisplatin
(CIS) represents a vital process in the elimination of
peritonitis carcinomatosa (PC). Liu et al., (2015) focused on
the efficacy of antibody-drug conjugates (ADCs) based on
alpha-amanitin, which were then targeted at the POLR2A
gene. It was observed that when the tumor suppressor gene,
TP53, is deleted, the nearby POLR2A was also deleted and
stopped cancer cell growth in mouse models of colorectal
cancer.
A recent study of Amanita phalloides inhibits the growth of
squamous cells carcinoma (SCC). A patient with pharyngeal
SCC is treated with Amanita toxins after failure of
conventional treatments with operations and radiations: The
state of the patient with SCC can be stabilized for five years.
Two years after beginning Amanita, Borrelia infection is
diagnosed, and additional treatment with Terebinthina
laricina occurs. The dose of Amanita can be reduced after
three years of treatment, indicating a reduction of tumor
cells (Riede, 2019).
Amanitin is RNA polymerase II (RNAPII) inhibitor in cells
within the extract of Amanita. RNAPII is utilized by
overexpression of switch genes that use RNAPII to 100% in
tumor cells. Fifty percent of RNAPII inhibition decreases the
activity of the tumor cells with no side effects. The immune
system can identify tumor cells and attack them thereby
opening up the prospect of recovery of healing and
stabilization. Amanita therapy may control a range of tumor
syndromes (Riede, 2012a, 2013a). This review focuses,
therefore on natural treatment strategies to treat cancer by
using the application of amanitin therapy.
II. AMATOXIN PROPERTIES
Amatoxin occurs as a heat-stable toxin for biochemical
categorization, which helps to preserve its three-dimensional
form at high temperatures. The enhanced toxicity of
amatoxins is because they are not responsive to enzymatic
hydrolysis. There are many subtypes of amatoxins, with
commonly alpha- amanitin (C39 H54 N10 O14 S, M=918.9)
and beta- amanitin (C39 H53 N9 O15 S, M= 919.9), and both
subtypes are not water-soluble as seen in figure (2) (Bever et
al., 2020).
There are not thermosensitive, which means they cannot be
destroyed by either cooking or freezing the mushrooms.
Moreover, they are gastroresistant (Garcia et al., 2015b) and
their metabolism is currently unknown.
Figure 2. Structure of amatoxins. R = NH2 for α-amanitin, R= OH for β-
amanitin (Bambauer et al., 2020.)
Amatoxins consist of eight toxic substances of eight amino-
acid derivatives grouped in a preserved pentacyclic

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9
configuration as shown in Figure (3) (Pahl et al., 2018).
Figure 3. The chemical structure of α-Amanitin in which eight amino acids
of α-amatoxins observed (Litten,1975)
α-Amanitin is a bicyclic octapeptide with a 6-
hydroxytryptathionine-(R)-sulfoxide cross-link and the
oxidized amino acids, 4,5-dihydroxy-isoleucine and trans-4-
hydroxy-proline (Matinkhoo et al., 2018).
Alpha-amanitin, the most deadly human amatoxin that
prevents protein synthesis that irreversibly binds to RNA
polymerase II and leads to cell death (Moor-Smith et al.,
2019).
III. TOXIC ASPECT AND THE HARMAL EFFECTS CAUSED
BY AMATOXIN
In the new classification, the amatoxins are classified in the
cytotoxic group (1A) (White et al., 2019) as they are responsible
for inhibiting RNA polymerase II and the transcription of
DNA into RNA by interfering with messenger RNA. This
brings about inhibition of protein synthesis, that causes to cell
necrosis (Edward et al., 2020). The first cells to be affected
are those with a maximum level of protein synthesis like
enterocytes, hepatocytes and proximal renal cells (Wieland,
1983). Studies in mice show that renal lesions only occur in
poisoning with low levels of amatoxins. In poisoning cases
with high levels, the subject die due to acute liver failure or
hypoglycemia before the renal lesions appear (Fiume et al.,
1969; Faulstich, 1979). Amatoxins are mainly eliminated in
the bile, but there is an enterohepatic cycle, which prolongs
the hepatoxic action (Broussard et al., 2001). Several studies
show that the LD50 of α-amanitin in humans is registered to
be 0.1 mg/kg per os (Brüggemann et al., 1996).
Bearing in mind that a sporophore of Amanita phalloides
(20– 25 g) can contain 5–8 mg of amatoxins (Faulstich,
1980), the ingestion of one A. phalloides mushroom is
theoretically a lethal dose for a 75 kg man. Toxicity cases of
amanita poisoning were recorded with an intake of 30 grams
of A. phalloides (Yilmaz et al., 2015).
Recently, (De Olano et al., 2020) estimated of 8.8% lethal rate
of recorded amatoxin toxic cases (n = 148) from 2008 to 2018
in the US, whereas registered 11.8% (1990–2008; n = 93) in
Portugal and under 20% (1994–2012; n = 624) in South China
(Diaz., 2018).
The same order of magnitude as found in mice in a study
published by Wieland in 1959 (Wieland, 1959) (LD50 = 0.1
mg/kg for α-amanitin and 0.4 mg/kg for β-amanitin by
intraperitoneal injection). Finally, it has been shown that the
concentration of amatoxins in the mushroom increases during
the first stages of the mushroom’s development, then
decreases during the mature stage (Hu et al., 2012). No
specific antidote exists for the amanitins. Treatment is
symptomatic (dialysis, activated charcoal hemoperfusion,
glucose/saline perfusion, etc.) (Wauters et al., 1978; Klein et
al., 1989). Only kidney or liver transplantation (depending on
the symptoms) can save a patient with multiple organ failure
(Klein et al., 1989; Meunier et al., 1995). Some authors
propose treatments such as thioctic acid (alpha lipoic acid)
(Kubicka, 1968; Becker et al., 1976., Rodrigues et al., 2017),
penicillin G (Moroni, et al., 1976), or silibinin (Baumgärtner
et al., 2011), which may be capable of limiting, if not
inhibiting, the amatoxins’ penetration into the liver cells
and/or interrupting the enterohepatic cycle of the toxins
(Enjalbert et al., 2002). However, these treatments have not
really been clinically proven and there is no signs for using
penicillin G or of thioctic acid. They are therefore not
considered as part of the protocol for treatment of amanitin
poisoning.
It seems clear that infants and small children are more
sensitive to these amanitin poisoning than adults, probably
because of their lower body mass: the same dose of toxins
ingested will be more toxic and the percentage of fatalities
will be higher in young subjects (Flament et al., 2020).
IV. CANCER THERAPY WITH AMANITA TOXINS
(AMANITIN)
During the last years, there was an increasing in the number
of studies that deals with the identification of as possible
cancer treatment by the injection of fungus toxic substances
directly into the tumor. It was mentioned, for example, the
therapy of Amanita is provided as dilutions of A. phalloides.
Their dilutions have been used for 300 years and a classical
homoeopathical sign of apprehension of death.
Approximately 50% of all RNAP molecules in 100 ml
dilutions of A. phalloides D2, are inhibited within all cells.
Thus, the patient is typically stabilized for years with
varying doses (Riede, 2016).
Numerous HOX genes, named switch genes, have been enhanced by
molecular events that induce tumor formation, which coded for
RNA polymerase II transcription factors (Riede, 2013a). Therefore,
RNA polymerase II is most effective in tumor cells than elsewhere.
Amanitin extract inhibits RNA polymerase II via an inhibition of
mRNA mechanism, leading to several types of tissue harms,
especially in intestinal mucosa, liver and kidneys. The toxin is
transferred to these tissues by enterohepatic circulation accompanied
by renal reabsorption (Riede, 2013a; Garcia et al., 2015c).

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Figure 4. Tumor formation biochemistry (Riede, 2013a). All switch genes
acts as transcription factors for RNA polymerase II (RNAP) and cause to be
100 % activity of RNAP in tumor cells. Partial inhibition of activity reduces
tumor cell activity with no influencing normal cells.
Partial inhibition of this enzyme induces tumor-cell response
inhibition, without extreme effects to somatic cells. The
compound amanitin inhibits RNAP in all cells.
Approximately 50% of molecule inhibition has little impact
on human body cells (Riede, 2007).
To expand the therapeutic range, dilutions of amanitin in A.
phalloides extract are given to a patient (Riede, 2010).
Amanita therapy stabilizes numerous tumor diseases
successfully:
A. Mammary Duct Cancer
Amanitin dilutions from A. phalloides are added to a patient
with mammary duct cancer. Various amanitin doses are used
for the detection of tumor markers. The previous tumor-
growth duplication period is three months. Nevertheless, the
patient could be recovered within 18 months, without further
tumor growth. There are still no significant signs, no hepatic
disruption and no continued deprivation of erythrocytes. This
latest tumor treatment principle demonstrates a strong
potential for medical treatment by using A. phalloides
dilutions (D2, D4) (Riede, 2011).
B. Leukemia
Leukemia tends to be commonly reported as anaemia disease,
i.e. erythrocytes absence. The leukocyte tumor growth
destroys the bone marrow, especially the erythropoietic stem
cells, which contributes to the depletion of erythrocytes. A
recent tumor therapy theory is introduced to this research:
Amanitin therapy. The amanitin retarded the tumor cells
activity. Monitoring leukocyte appearance contributes to
dosing in the blood. When the number of cells rises and the
patients overall health is well, a maximum dosage is added and
vice versa. Each maximum dose interval (i.e., 80ml of D2
within several months) began with low levels of erythrocytes
(Riede, 2010).
Figure 5. B-cell chronic lymphatic leukemia (B-CLL) treatment (Riede,
2010). The levels of the leukocyte cell numbers in blood (Log B-cells [/mL
blood]) over time (solid line). Before amanita therapy, the cells observed
slowly growth at 21 months duplication period (elongated as broken line).
Amanita therapy began at time zero. Lactate dehydrogenase (LDH) levels
(dotted line) vary with leukocyte levels. When a maximum dose is given,
leukocyte levels declines and LDH levels go up, meaning tumor cells lysis.
Due to amanitin uptake, the numbers of leukocytes reduces in
the blood and certain cells lysis rises lactate dehydrogenase
(LDH). This repeatedly helps in the erythrocyte level
recovery in a short period within the blood. In the absence of
amanitin, the LDH values stay in the appropriate range,
suggesting that the immune system does not lysis tumor cells
effectively. With amanitin uptake, the count of leukocyte
cells rises, and cell lysis occurs, this means the tumor
leukocytes is possibly lysis. This lysis indicates that amanitin
is not only can disrupt the tumor growth activity, but may
also modify the expression of antigen, which may make the
immune system more effective to destroy the tumor cells
(Riede, 2015). After the starting of therapy for eight months,
the leukocyte count decreases to 0.45×105/µl, correlating with
lymphocytic inflammatory signs. Then, the leukocyte value
rises to 1.08×105/µl within one week. This duplication is not
supposed to occur from cell growth; the period for
duplication is 21 months. Additionally, leukocyte migration
is also mentioned. Probably, the leukocyte count declines in
blood, which may not only from cells lysis, but also from
periphery migration. Therefore, Amanitin can affect the
leukocytes migration, as seen in Figure 3 (Riede, 2010).
About 1-00ml of A. phalloides D2 annually will arrested B-
CLL tumor growth. Amanita therapy frequently has good
therapeutic or prophylactic results in a number of other
tumors, including mammary carcinoma, tongue root tumor
and colon carcinoma (Riede, 2007). The somatic cells
activity, particularly the immune cells, are not affected by
this therapy. Amanitin inhibits the tumor cells activity, and
then it lyses and migrates. Therefore, A. phalloides
homoeopathic dilutions provide good cancer treatment tools
(Riede, 2010, 2015).
C. Colon Carcinoma and Thyroid Carcinoma
Amanita therapy and dietary patterns appear to give several
patients new possibilities. Changing dietary patterns by
adding 70 gram sugar daily results in increased tumor marker
values. The tumor marker values decline after diet without
sugar and decreased carbohydrates. Despite amanita tumor
therapy with sugar, the tumor activity increases; hence, low

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11
dietary carbohydrates help the therapy. Therefore, amanita
therapy as a lifelong treatment is recommended. Scientific
research suggests a balanced cancer- protecting diet. Some
regimens utilize a diet with reduced carbohydrate comprising
unprocessed materials (Riede, 2013b).
The sugar consumption effect on tumor cell activity may be
observed by monitoring tumor markers. Although the thyroid
cancer cells are less affected, rectal tumor cells show a triple
increase in their activity. A supportive dietary is used as
cancer protection and cancer patients such as vegetables,
fruits, wild herbs, rich unsaturated fatty acids and plant oils
(Riede, 2013b).
D. Prostate Cancers
Prostate cancer is considered one of the most common
cancers among men, which appears over fifty. The signs,
physical examination, prostate-specific antigen (PSA), or
biopsy can be recommended for diagnosis (Riede, 2017).
Prostate cancer screening is addressed among men older than
50. The dilutions of A. phalloides (D2, D4), partially very
little dose i.e., some D4 drops per day, are adequate to
maintain PSA levels. In 2010, fear of the tumor contributes to
voluntary of amanita uptake. After three years from using
therapy, all three patients began feeling well and they avoided
taking amanita. The patients may ignore it in order to maintain
a low serum level, PSA values increase and involve 100 ml of
D2 intake in two months (Riede, 2012b).
Amanitas long-term desire for physical symptoms needs a
good leadership. Further research will show more facets of
this latest possibility (Riede, 2012b, 2016).
V. CONCLUSIONS
In recent years, α-amanitin of amanita therapy received an
increased attention as a gentle medical treatment in cancer
therapy is more suitable. Through my readings to different
researchers' reports, no severe side effects happen and no
clinical symptoms when the patient used the amanita therapy.
Amanitin inhibits the activity of tumor cells. Thus, α-amanita
can first be used as a tumor-specific therapy. Antiandrogen
drugs, chemical therapy, radiation or prostatectomy can be
used at subsequent levels.
CONFLICT OF INTEREST
The author declares no conflict of interest.
ACKNOWLEDGEMENTS
The author would like to thank Mustainsiriyah University
(www.uomustansiriyah.edu.iq) Baghdad, Iraq for its support
in the present work.
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