Evidence-Based Review of BioBran/MGN-3 Arabinoxylan Compound as a Complementary Therapy for Conventional Cancer Treatment

Abstract

Introduction:
Conventional cancer treatment, including surgery, chemotherapy, and radiotherapy, may not be sufficient to eradicate all malignant cells and prevent recurrence. Intensive treatment often leads to a depressed immune system, drug resistance, and toxicity, hampering the treatment outcomes. BioBran/MGN-3 Arabinoxylan is a standardized arabinoxylan concentrate which has been proposed as a plant-based immunomodulator that can restore the tumor-induced disturbance of the natural immune system, including natural killer cell activity to fight cancer, complementing conventional therapies.

Objectives:
To comprehensively review the available evidence on the effects and efficacies of MGN-3 as a complementary therapy for conventional cancer treatment.

Methods:
Systematic search of journal databases and gray literature for primary studies reporting the effects of MGN-3 on cancer and cancer treatment.

Results:
Thirty full-text articles and 2 conference abstracts were included in this review. MGN-3 has been shown to possess immunomodulating anticancer effects and can work synergistically with chemotherapeutic agents, in vitro. In murine models, MGN-3 has been shown to act against carcinogenic agents, and inhibit tumor growth, either by itself or in combination with other anticancer compounds. Fourteen successful MGN-3 treated clinical cases were found. Eleven clinical studies, including 5 nonrandomized, pre-post intervention studies and 6 randomized controlled trials (RCTs) were located. Reported effects include enhanced immunoprofile, reduced side effects, improved treatment outcomes; one RCT established significantly increased survival rates. There are no reports on adverse events on MGN-3. Most of the clinical trials are small studies with short duration.

Conclusion:
There is sufficient evidence suggesting MGN-3 to be an effective immunomodulator that can complement conventional cancer treatment. However, more well-designed RCTs on MGN-3 are needed to strengthen the evidence base.

Full text

https://doi.org/10.1177/1534735417735379
Integrative Cancer Therapies
1 –14
© The Author(s) 2017
Reprints and permissions:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/1534735417735379
journals.sagepub.com/home/ict
Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-
NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use,
reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open
Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
Review Article
Introduction
Cancer is a leading cause of death worldwide with an esti-
mated 14.1 million new cases and 8.2 million cancer
deaths occurring worldwide in 2012.1 Conventional can-
cer treatment, including surgery, chemotherapy, and
radiotherapy, which focuses on eliminating cancer cells,
can be effective in the short term.2 However, such
approaches are insufficient to eradicate all malignant
cells, especially in advanced cancer, resulting in recur-
rence. Repeated cycles of such intensive treatment can
suppress the immune system, promote chemotherapy-
and radiotherapy-resistant tumors, as well as local and
systemic toxicity.3 Immunotherapy, which uses nonchem-
ical, biological substances called biological response
modifiers (BRMs) or immunomodulators to induce,
boost, or restore the body’s natural defense capability to
fight cancer,4 is now being acknowledged as an important
735379ICTXXX10.1177/1534735417735379Integrative Cancer TherapiesOoi et al
review-article20172017
1Centre of Complementary & Alternative Medicine, Singapore
2Charles Sturt University, Bathurst, New South Wales, Australia
3St George Hospital, Sydney, New South Wales, Australia
Corresponding Author:
Sok Cheon Pak, School of Biomedical Sciences, Charles Sturt University,
Panorama Avenue, Bathurst, New South Wales 2795, Australia.
Email: spak@csu.edu.au
Evidence-Based Review of BioBran/
MGN-3 Arabinoxylan Compound as a
Complementary Therapy for
Conventional Cancer Treatment
Soo Liang Ooi, MMath, BHSc (Comp Med)1, Debbie McMullen, BHSc (Comp Med)2,
Terry Golombick, PhD, Dipl Nut3, and Sok Cheon Pak, PhD2
Abstract
Introduction: Conventional cancer treatment, including surgery, chemotherapy, and radiotherapy, may not be sufficient to
eradicate all malignant cells and prevent recurrence. Intensive treatment often leads to a depressed immune system, drug
resistance, and toxicity, hampering the treatment outcomes. BioBran/MGN-3 Arabinoxylan is a standardized arabinoxylan
concentrate which has been proposed as a plant-based immunomodulator that can restore the tumor-induced disturbance
of the natural immune system, including natural killer cell activity to fight cancer, complementing conventional therapies.
Objectives: To comprehensively review the available evidence on the effects and efficacies of MGN-3 as a complementary
therapy for conventional cancer treatment. Methods: Systematic search of journal databases and gray literature for primary
studies reporting the effects of MGN-3 on cancer and cancer treatment. Results: Thirty full-text articles and 2 conference
abstracts were included in this review. MGN-3 has been shown to possess immunomodulating anticancer effects and can work
synergistically with chemotherapeutic agents, in vitro. In murine models, MGN-3 has been shown to act against carcinogenic
agents, and inhibit tumor growth, either by itself or in combination with other anticancer compounds. Fourteen successful
MGN-3 treated clinical cases were found. Eleven clinical studies, including 5 nonrandomized, pre-post intervention studies and
6 randomized controlled trials (RCTs) were located. Reported effects include enhanced immunoprofile, reduced side effects,
improved treatment outcomes; one RCT established significantly increased survival rates. There are no reports on adverse
events on MGN-3. Most of the clinical trials are small studies with short duration. Conclusion: There is sufficient evidence
suggesting MGN-3 to be an effective immunomodulator that can complement conventional cancer treatment. However,
more well-designed RCTs on MGN-3 are needed to strengthen the evidence base.
Keywords
MGN-3, BioBran, Arabinoxylan, Ribraxx, systematic review, cancer, complementary medicine, chemotherapy,
chemoprotective, immunomodulation, immunotherapy, adjunct therapy, rice bran, adenocarcinoma, carcinogenesis
Submitted June 11, 2017; revised August 6, 2017; accepted September 12, 2017

2 Integrative Cancer Therapies
cancer treatment strategy that can work in combination
with conventional therapies.5,6
BioBran/MGN-3 Arabinoxylan (MGN-3) is a natural
blend of hemicelluloses derived from partially hydrolyzed
rice bran with shiitake mushroom enzymes (Lentinus edodes
mycelia extract). It is developed and manufactured in Japan
by Daiwa Pharmaceutical Co, Ltd, and marketed worldwide
as a nontoxic food supplement under different brand names
such as BioBran (Globally), Lentin Plus (Japan/Asia),
Ribraxx (Australia/New Zealand), BRM4 (United States),
and others.7 The main chemical structure of MGN-3 is an
arabinoxylan with a xylose in its main chain and an arabi-
nose polymer in its side chain. The result of a methylation
analysis suggests that a complex structure of heteropolysac-
charide (arabinogalactan, arabinoxylan, arabinan, β-1,3:1,4-
glucan) is behind the immunomodulatory mechanisms and
antitumor activity of MGN-3.8 MGN-3 has been promoted
as a plant-based BRM for enhancing the depleted immune
system during and after conventional cancer treatment,
claiming support from research findings and good clinical
results.9
Objectives
To perform a comprehensive literature review of the available
evidence on the effects and efficacies of MGN-3 as a comple-
mentary therapy to support conventional cancer treatment.
Methods
Systematic searches were conducted using research databases
including PubMed, ProQuest, MEDLINE, EBSCOhost (All),
Cochrane CENTRAL, Embase, and EBM Review (All) with-
out any restriction in year of publications. Keywords used
include “MGN-3,” “BioBran,” “arabinoxylan,” “rice bran,”
and “plant immunomodulators” in combination with “cancer”
or “chemotherapy.” Additionally, the collected papers on
MGN-3 published by BioBran Research Foundation,10 the
official website of MGN-3 (https://biobran.org), the English
language website of Daiwa Pharmaceutical (http://www.
daiwa-pharm.com/english), and the references of included
articles were searched manually. The criteria for inclusion
were (1) primary research reports published in English inclu-
sive of in vitro, in vivo, clinical study, and case reports and (2)
research studies focused on the effects of MGN-3 on any form
of cancer alone or as a combination therapy, or the combined
effects of MGN-3 with one or more chemotherapeutic agents,
or the effects of MGN-3 on cancer patients.
Results
Search Results
Systematic searches were conducted by 2 authors (DM and
SLO) independently between March to May 2017. The
searches yielded 166 unique records after duplications were
removed. After initial screening, 48 articles were assessed
for eligibility. Sixteen articles were excluded with reasons
as follows: duplication (5),11-15 not cancer focused (7),16-22
not primary study (3),23-25 and 1 case report article pub-
lished in Japanese was also excluded.26 Thirty full-text arti-
cles and 2 conference abstracts were included in this review,
consisting of 7 in vitro studies;27-33 1 article reporting results
from both in vitro and in vivo studies;34 7 in vivo stud-
ies;35-41 6 clinical case reports;42-47 and 11 clinical stud-
ies,48-58 with one of them also including case reports of
selected follow-up patients.48 The literature search flow is
summarized in Figure 1.
In Vitro Studies
The characteristics of the in vitro studies are listed in Table
1. In these studies, both the immunomodulating and syner-
gistic anticancer effects of MGN-3 were demonstrated.
Immunomodulating Anticancer Effect. The growth of squa-
mous cell carcinoma (SCC13) was arrested after incubating
in MGN-3 for up to 72 hours.27 Tumor cell growth was
arrested with the increase in apoptosis through the CD95
death receptor pathway. An increase of more than 200% in
the rate of apoptosis of MGN-3 pretreated tumor cells
(human T cell leukemic HUT 78) to the agonistic anti-CD95
antibody was observed. The effect was shown to be dose
dependent.28 Compared with resting NK cells, MGN-3
stimulated NK cells induced a higher expression of the acti-
vation associated receptors CD25 and CD69. Statistically
significant increases in cytotoxicity of MGN-3 stimulated
NK cells against several cancer cells were consistently
observed, but cytotoxicity was absent against normal cells.34
Synergistic Anticancer Effect. MGN-3 works synergistically
with natural anticancer substances such as Saccharomyces
cerevisiae (Baker’s yeast) and curcumin, as well as chemo-
therapy drugs (daunorubicin and paclitaxel) in a dose-
dependent manner.
Ghoneum and Gollapudi29,30 confirmed the ability of
MGN-3 to accelerate the phagocytosis of S cerevisiae in
breast cancer and enhance the yeast-induced apoptosis of
breast cancer cells (BCCs).29,30 After incubating different
BCCs (MCF-7, ZR-75, HCC70) with heat-killed S cerevi-
siae and MGN-3, a 2-fold increase was observed in the
attachment and uptake of yeast by the treated MCF-7 cells,
compared with untreated cells, in a time-dependent man-
ner.30 Treatment with MGN-3 also resulted in a 1.8- to 2.5-
fold increase in the percentage of apoptosis in different
BCC cell lines.29 The yeast-phagocytosis and apoptosis
effect was not present in nontumorgenic breast cells.30
Culturing human multiple myeloma (MM) cell line
U266 with MGN-3 (50 or 100 μg/mL) and curcumin

Ooi et al 3
(2.5-10 μM) for 3 days, Ghoneum and Gollapudi32 also
showed that the proliferation of U266 cells was inhibited by
MGN-3 alone or curcumin alone.32 However, an optimal
synergistic effect was observed with a combination of 100
μg/mL MGN-3 plus 10 μM curcumin, characterized by an
87% decrease in U266 cell numbers and a 2.6-fold increase
in the percentage of apoptotic U266 cells.32
The survival rates of BCCs (MCF-7 and HCC70 cells)
cultured for 3 days with different concentrations of dauno-
rubicin (1 × 10−9 to 1 × 10−6 M) with or without MGN-3
(100-1000 μg/mL) were measured.31 MGN-3 increased the
accumulation of daunorubicin in the cancer cells and sig-
nificantly decreased the cell survival of MCF-7 (by 5.5-
fold) and HCC70 cells (by 2.5-fold) as compared to BCCs
treated with daunorubicin alone.31 Through a similar exper-
imental design in a later study, MGN-3 was demonstrated to
sensitize non-metastatic human BCC MCF-7 and metastatic
murine BCC 4TI to paclitaxel and to increase their suscep-
tibility to the chemotherapeutic agent by over 100-fold. The
synergistic effects include causing DNA damage, enhanc-
ing apoptosis, and inhibiting cell proliferation of BCCs.33
In Vivo Studies
The characteristics of the in vivo studies are listed in Table
2. Through various murine models, these studies showed
that MGN-3 could potentially prevent cancer, inhibit its
growth, and work synergistically with other chemothera-
peutic agents.
Preventive Effect Against Carcinogenic Agents. Significantly
lower incidences of dysplasia and gastric cancer were
observed in male Wistar rats fed with carcinogen methylni-
tronitrosoguanidine (MNNG) plus MGN-3, compared with
those administered MNNG alone.39 The preventive effects
of MGN-3 observed include suppression of Ki-67 tumor
marker, upregulation of apoptotic gastric cancer cells via
the mitochondrial-dependent pathway, and protection
against decrease in lymphocyte levels.39
Male albino rats pretreated with MGN-3 before receiv-
ing carcinogenic N-nitrosodiethylamine (NDEA) and car-
bon tetrachloride (CCl4) showed a significant reduction in
liver tumor incidence, marked decrease in the percentage of
Figure 1. Literature search flow diagram (based on PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses]
2009).

4 Integrative Cancer Therapies
preneoplastic foci in hepatic parenchyma, and inhibition in
the development of hepatocellular carcinoma, compared
with controls. MGN-3 treated rats were also able to main-
tain close to normal levels of hepatic diagnostic markers.41
Inhibition of Cancer Growth. Female Swiss albino mice
bearing solid Ehrlich carcinoma (SEC) tumors were
treated with intraperitoneal injections of MGN-3.37,38
Compared with controls, MGN-3-treated mice exhibited
a significant delay in tumor growth measured by tumor
volume (63.27%) and tumor weight (45.2%), without any
observed adverse side effects due to the treatment.37 The
anticancer mechanisms of MGN-3 were shown to be
immunomodulating through upregulation of tumor necro-
sis factor-α (TNF-α) and interferon-γ (IFN-γ), and down-
regulation of interleukin-10 (IL-10), as well as inducing
apoptosis in the SEC cells.37 Elevated levels of antioxi-
dant enzymes such as superoxide dismutase, glutathione
peroxidase, catalase, and glutathione-S-transferase, in
blood and liver of MGN-3-treated animals comparable to
the normal levels were observed.38 The effects of MGN-3
treatment were more pronounced in mice that were treated
earlier rather than later.
NOD-scidIL-2Rgnull mice inoculated with neuro-
blastoma cells were treated with intravenous NK
cellular therapy using either fresh NK cells or NK cells
activated with MGN-3 overnight. The mice treated with
MGN-3 activated NK cells had upregulated NK cell
activation markers, significant neuroblastoma growth
inhibition, and higher survival rate compared to control
groups.34
Synergistic Effects With Chemotherapeutic Agents. Female
Swiss albino mice inoculated with Ehrlich ascites carci-
noma cells were treated with paclitaxel only, MGN-3 only,
or MGN-3 plus paclitaxel. Tumor volumes were signifi-
cantly suppressed in MGN-3 plus paclitaxel group (88%
smaller relative to controls), compared with paclitaxel only
group (77%), and MGN-3 only group (59%).40
MGN-3 may also potentially protect against the adverse
effects of chemotherapeutic agents. Sprague-Dawley
derived albino rats fed with MGN-3 were healthier, gained
weight, and had a lower incidence of diarrhea and gross
intestinal pathology, after being administered a dose of
either cisplatin or doxorubicin, compared with control.35
Similarly, MGN-3 given either orally or intraperitoneally
to BALB/c female mice was shown to protect them from
severe weight loss associated with the injection of
cisplatin.36
Table 1. Characteristics of the Included In Vitro Studies.
No. Study Target Cell MGN-3 (μg/mL) Combined Agent Duration Outcomes
1 Ghoneum et al
(2000)27–Abstract only
Squamous cell carcinoma
(SCC13)
Not specified Nil 72 h 30% decrease in cell number after 48 h and
50% decrease at 72 h of culture as compared
with control. Increases in intracellular levels
of IL-10 and 12, but not INF-γ
2 Ghoneum and Gollapudi
(2003)28
Human leukemic cells
(HUT 78)
100, 300, 1000 Agonistic anti-CD95
antibody
3-24 h 200% increase in apoptotic cells pretreated
with MGN-3 compared with control
3 Ghoneum and Gollapudi
(2005)29
Human breast cancer cells
(BCC) MCF-7, ZR-75,
HCC70
100, 500, 1000 Saccharomyces
cerevisiae at a cell to
yeast ratio of 1:10
2 h Dose-dependent effects of accelerated yeast
phagocytosis by MCF-7 cells and enhanced
apoptosis of cancer cells MCF-7 (2-fold),
ZR-75 (2.5-fold), and HCC70 (1.8-fold) by
MGN-3, compared with control
4 Ghoneum and Gollapudi
(2005)30
Monolayer BCC MCF-7
and nontumorigenic
breast epithelial (MCF-
10A)
100 S cerevisiae at a cell to
yeast ratio of 1:10
1-4 h MGN-3 increased the yeast-phagocytosis of
MCF-7 cells by 2-fold, and enhanced yeast-
induced apoptosis compared with control.
No phagocytosis of yeast by MCF-10A cells
observed
5Gollapudi and Ghoneum,
(2008)31
Human BCC MCF-7 and
HCC70
100, 500, 1000 Daunorubicin (1 × 10−9
to 1 × 10−6 M)
3 days MGN-3 increased susceptibility of MCF-7 (5.5-
fold) and HCC70 (2.5-fold) to daunorubicin.
Increased accumulation of daunorubicin in
the cancer cells were observed
6 Ghoneum and Gollapudi
(2011)32
Human multiple myeloma
(U266) cells
50 or 100 Curcumin (2.5-10 μM) 3 days 87% decrease in cell number and a 2.6-fold
increase in the percentage of apoptotic
U266 cells by 100 μg/mL MGN-3 plus 10 μM
curcumin. The effect was dose dependent
7 Ghoneum et al (2014)33 Nonmetastatic human
BCC (MCF-7) and
metastatic murine BCC
(4T1)
100, 250, 500,
600, 750,
1000
Paclitaxel (1 × 10−1 to 1
× 10−6 M)
24, 48 h MGN-3 increased the susceptibility of both
types of cancer cells to paclitaxel by over
100-fold; achieved through DNA damage,
enhanced apoptosis, and inhibition of cell
proliferation in 4T1 cells
8 Pérez-Martínez et al
(2015)34
Erythroleukemia (K562);
Jurkat T lymphoid
leukemia; Ewing sarcoma
(A673); neuroblastoma
(NB1691)
100 NK cells Overnight MGN-3 stimulated NK cells induced a higher
expression of the activation associated
receptors CD25 and CD69; increased NK
cell cytotoxic activity against all cell lines
tested; and promoted NK cell expansion

Ooi et al 5
Case Reports
The included case reports42-48 narrated a total of 14 success-
ful MGN-3-treated clinical cases. The patient characteris-
tics and outcomes are summarized in Table 3.
Most patients were older than 50 years with only 2
patients of younger age, and 2 patients with age unreported.
Typ es of primary cancer in these cases include leukemia
(2), prostate (1), breast (1), colorectal (2), pancreas (1),
liver (3), lung (2), skin (1), and ovary (1). Most patients
started taking MGN-3 either in conjunction with conven-
tional cancer treatment, or after completion of conventional
treatment. Dosages of MGN-3 reported in these cases were
Table 2. Characteristics of the Included In Vivo Studies.
No. Study Animal Model MGN-3 Dosage Combined Agent Duration Outcomes
1 Jacoby et al (2001)35 Sprague-Dawley derived albino
rats
Daily oral dosing of 5 or 50 mg/kg 1 × intraperitoneal (IP) dose
of cisplatin or doxorubicin
on day 3
11 days Rats receiving MGN-3 were healthier;
gained weight and had a lower
incidence of diarrhea and gross
intestinal pathology compared with
control
2 Endo and Kanbayashi
(2003)36
BALB/c female mice 0.1 mL at 10 mg/mL in water or by
IP daily 1 wk before cisplatin
Single shot of cisplatin (0.1
mL at the concentration
of 15 mg/kg)
28 days MGN-3 (both orally and IP) showed
accelerated protection against
severe loss of body weight of mice
due to cisplatin. The result was
statistically significant
3 Badr El-Din et al
(2008)37
Female Swiss albino mice
inoculated with Ehrlich
ascites carcinoma (EAC) cells,
bearing solid tumors
MGN-3 dissolved in 0.9% saline
given via IP or intratumoral
injections at 40 mg/kg body
weight (BW) daily for 5 wk
Nil 5 wk MGN-3 significantly delayed growth
in both tumor volume (63.27%) and
tumor weight (45.2%) compared
with control, through increased
apoptosis of EAC cells (1.8-
fold), influenced plasma cytokine
production, downregulated immune
suppressing cytokine IL-10, and
increased NK cells activity. No
adverse side effects due to MGN-3
treatment were observed
4 Noaman et al (2008)38 Female Swiss albino mice
inoculated with EAC cells,
bearing solid tumors
MGN-3 dissolved in 0.9% saline
given via IP at 25 mg/kg BW, 6
times a week from day 4 or day
11 after inoculation and end at
day 25
Nil 25 days MGN-3 suppressed the growth
of tumors; normalized lipid
peroxidation level, augmented
glutathione contents, and enhanced
antioxidant enzymes activity in
blood, liver, and tumor tissue. More
pronounced effects were observed
when treated by MGN-3 as early
as day 4
5 Pérez-Martínez et al
(2015)34
NOD-scidIL-2Rgnull mice
injected intravenously (IV)
with NB-1691luc 2 × 105
neuroblastoma cells
100 μg/mL overnight for activation
of NK cells
NK cells (fresh or MGN-3
activated). NK cellular IV
therapy began 7 days after
tumor cells inoculation,
twice a week for 4 wk
4 wk MGN-3 stimulated NK cells
inhibited neuroblastoma growth
and increased survival compared
with control. The results were
statistically significant
6 Badr El-Din et al
(2016)39
Male Wistar rats 1 dose of 40 mg/kg BW via IP
injection every other day a total
of 8 mo
Orally administered
carcinogenic MNNG
(N-methyl-N′-nitro-N-
nitrosoguanidine) at 200
mg/kg BW daily for 2
weeks
8 mo MGN-3 significantly lowered
incidence of dysplasia and gastric
cancer when combined with
MNNG; effects observed include
suppression of Ki-67 tumor marker,
upregulation of apoptotic gastric
cancer cells via mitochondrial-
dependent pathway, and protection
against decrease in lymphocyte
levels
7 Badr El-Din et al
(2016)40
Female Swiss albino mice
inoculated with EAC cells,
bearing solid tumors
1 dose of 40 mg/kg BW via IP
injection every other day
starting from day 8 until day 30
Paclitaxel at a dose of 2 mg/
kg BW every other day
starting from day 8 until
day 30
30 days MGN-3 plus paclitaxel significantly
suppressed tumor volume (88%)
compared with paclitaxel only
(77%) or MGN-3 only (59%).
Inhibition of tumor growth was
associated with reduced cancer
cell proliferation, increased DNA
damage and apoptosis
8 Badr El-Din et al
(2016)41–Abstract
only
Male albino rats 25 mg/kg BW 5 times/week IP
for 2 wk prior to receiving
carcinogens and continued for
20 wk
Carcinogenic NDEA (N-
nitrosodiethylamine) (200
mg/kg BW) single dose
IP, plus promoter CCl4
(3 mL/kg BW) weekly
subcutaneously for 6
weeks
20 wk MGN-3 inhibited
hepatocarcinogenesis induced by
NDEA and CCI4 via induction of
apoptosis and inhibition of cancer
cell proliferation; maintained AST,
ALT, ALP, and gamma-GT levels
close to normal values

6 Integrative Cancer Therapies
Table 3. Patient Characteristics and Outcomes of the Included Clinical Case Reports.
No. Report Patient, Age Cancer
Conventional and Adjunct
Treatment MGN-3 Dosage Outcomes
1 Ghoneum and Brown
(1999)48
Male, 39 y Acute myelogenous
leukemia
Chemotherapy 3 g/d after
chemotherapy
White blood cells (WBCs) count at 5.6 ×
109/L after completion of chemotherapy
and maintained. NK activity increased
from 7.9 LUs to 113 LUs after 1 wk of
MGN-3 and maintained at high level for
4 y at the point of reporting
Male, 52 y Acute myelogenous
leukemia
No conventional
treatment
3 g/d WBCs count at 18.7 × 109/L
pretreatments. Reduced to 11 × 109/L
after 1 mo. Condition stable for 4 y at
the point of reporting
Male, age
unknown
Prostate cancer Hormonal therapy 3 g/d after
hormonal
therapy
Prostate-specific antigen (PSA) level at
0.1 after hormonal therapy. PSA level
remained within normal range for 4 y at
the point of reporting
Female, age
unknown
Recurrence breast
cancer
Surgery and
chemotherapy
3 g/d after
completion of
chemotherapy
NK cell activity increased 2-fold from
baseline (16.4 LUs) after 1 wk. Further
increased to 128 LUs and remained
high 4 y at the point of reporting.
No evidence of recurrence seen in
computed tomography (CT) scans or
biopsies
2 Kawai (2004)42 Female, 64 y Umbilical metastasis of
recurrent colorectal
cancer (Sister Mary
Joseph’s Nodule
[SMJN])
5-Fu 500 mg, Isovorin 250
mg (10A), Topotecin 40
mg administered once a
week from 19th month
onward
3 g/d for first
18 mo; 6 g/d
subsequently
Patient survived 2 y and 2 mo since
detection (typical survival time: 2 wk to
11 mo) and was still alive at the time of
reporting. MGN-3 helped to prolong life
and improved quality of life
3 Kaketani (2004)43 Male, 64 y Terminal pancreatic
cancer with distant
metastasis
Oral anticancer drugs
(Furtulon 1200 mg/time
and Endoxan 200 mg/
time)
ACM π water (MRN-
100A) 300 mL/d
6 g/d Initial prognosis was 3 mo of life. 5 mo
after treatment, CT images showed
pancreatic cancer to be unmeasurable
and reduced liver metastasis similarly.
Endoscopy 12 mo after treatment
showed almost no abnormality. Patient
survived 17 mo with a normal life and
died of hematemesis not related to
cancer
4 Okamura (2004) 44 Male, 67 y Liver cancer with
intestinal metastasis
1 y of treatment at
another hospital
previously
Intravenous (IV) infusion
of Bio-reproducing
Protein (BRP) once
every 4 wk
3 g/d
administered
for 157 days
Initially pronounced to have 1 mo to live.
The general condition, tumor markers,
and immunocompetence improved
after 2 y. Patient entered 7th year of
treatment at the time of reporting living
a normal working life and received
treatment on outpatient basis
Male, 65 y Liver cancer Conventional treatment
at 2 other medical
institutions previously
IV infusion of BRP once
every 4 wk
3 g/d for 72 days Liver cancer marker and
immunocompetence improved after 6
mo. Liver function markers raised initially
and decreased at 1 y, with jaundice
disappeared, appetite improved, no
pain occurred through to 1 y 11 mo of
treatment
Female, 71 y Liver cancer Initial treatment at
another hospital with
poor results
IV infusion of BRP once
every 4 wk
3 g/d for 392
days
Hepatic tumor markers decreased after
6 mo of treatment. Clinical symptoms
improved and jaundice disappeared
Female, 76 y Lung cancer
(adenocarcinoma
spread through both
lung fields)
Initial treatment at
another hospital with
no improvement
IV infusion of BRP once
every 4 wk
3 g/d for 128
days
Lung tumor maker (tissue polypeptide
antigeny [TPA]) decreased after
4 mo. Coughing decreased.
Immunocompetence (TK activity)
gradually improved
Male, 58 y Colorectal cancer with
liver metastasis
Underwent surgery at
another hospital
IV infusion of BRP once
every 4 wk
3 g/d for 77 days Liver function (glutamic-pyruvic
transaminase [GPT]) improved rapidly
and immunocompetence (TK activity)
stabilized after 1 mo of treatment.
Patient continued to work with no
subjective symptoms at the time of
reporting
(continued)

Ooi et al 7
3 g/d, 6 g/d, and 45 mg/kg per body weight (BW), adminis-
tered orally. In some cases, MGN-3 was combined with
other forms of complementary therapies, including ACM π
water,43 Bio-reproducing Protein (BRP),44 and mistletoe
lectin.46,47
In nonterminal cancer cases, reported results were:
improvements in tumor markers, immunocompetence pro-
file, and initial symptoms44; patient conditions were stable
with no sign of cancer recurrence at follow-up48; and
patients showed improved quality of life (QoL) reported as
subjective improvements in sleep, appetite, digestion, phys-
ical activity and decrease in anxiety and pain; reduced
adverse effects during chemotherapy, and cancer remis-
sion.46,47 In one self-treated case, the patient refused further
conventional treatment for metastatic lung tumor after the
initial removal of his skin lesion. The metastatic lung tumor
became undetectable after 34 months of self-treatment with
MGN-3.45 In 3 cases of terminal cancer with poor progno-
sis, the patients were reported to be able to survive much
longer beyond the initial estimated lifespans with improved
QoL, and even normal working lives.42-44
Clinical Studies
Eleven clinical studies were included in this review. Among
the 11 clinical studies, 5 are nonrandomized, pre-post inter-
vention studies,48,50,51,57,58 and 6 are randomized controlled
trials (RCTs).49,52-56 The characteristics of these studies are
summarized in Table 4 (nonrandomized studies) and Table
5 (RCTs).
Nonrandomized, Pre-post Intervention Studies. The immuno-
modulating effects of MGN-3 were examined by Ghoneum
and Brown.48 Thirty-two cancer patients (various malignan-
cies) with depressed NK cell activity post conventional can-
cer treatment were treated with MGN-3 for 2 weeks. A
significant increase in NK cell activity up to tenfold was
observed. Increase in NK cell granularity and binding
capacity, improvement in T and B cell proliferation in vivo,
and improvement in tumor-associated antigens were
observed in a selected number of patients.48 Similarly,
Tsunekawa50 reported normalization of NK cell activity and
improvement in white blood cell (WBC) count in a small
study of 16 cancer patients. These were patients with vari-
ous malignancies who went through conventional cancer
treatment before starting the MGN-3 therapy for 6 months.
No subjective or objective adverse effects were recorded.
In another study, however, no substantial change in NK
cell counts was observed in 22 cancer patients after taking
MGN-3 for 2 months.51 Instead, an increase in the T helper
(Th) lymphocytes to T regulatory (Treg) lymphocytes
(CD4+ CD25+) ratio (Th:Treg) was recorded, demonstrat-
ing the effect of anticancer immunity restoration of the
MGN-3 therapy. Nonetheless, due to the small number of
patients, the results were not statistically significant.51 More
recently, Golombick et al57 reported that the combination
therapy of MGN-3 and curcumin helped 20 patients with
early B-cell lymphoid malignancies to delay disease pro-
gression by increasing neutrophil count and reducing the
raised erythrocyte sedimentation rate (ESR). No significant
change in NK cell counts was detected. Again, results from
this study lack statistical power.
No. Report Patient, Age Cancer
Conventional and Adjunct
Treatment MGN-3 Dosage Outcomes
5 Markus et al (2006)45 Male, 68 y Metastatic
hemangiopericytoma
of the skin with
multiple pulmonary
nodules
Wide local excision for
removal of the skin
lesion
Patient refused further
conventional treatment
for pulmonary nodules
Self-administered
with unknown
dosage
Lung masses steadily decreased in size by
serial imaging and became undetectable
after 34 mo of MGN-3 therapy
6 Hajto et al (2015)46 Female. 28 y Left ovary sarcoma
and endometrium
sarcoma with a
metastasis in the
right ovary
Removal of left ovary
followed with
hysterectomy and
adnexectomy
Chemotherapy with a
CYVADIC protocol
commenced 4 wk after
second surgery
Started 0.75 ng/kg
mistletoe lectin twice a
week since 3rd cycle of
chemotherapy
45 mg/kg given
twice a week
started at
3rd cycle of
chemotherapy
A rapid improvement of quality of
life was observed after starting the
immunotherapy (lectin + MGN-3).
Patient was better able to tolerate the
next 3 cycles of chemotherapy. At the
time of reporting, the patient was tumor-
free after 5 y
7 Hajto et al (2016)47 Female, 74 y Inoperable lung
adenocarcinoma
4 cycles carboplatin and
paclitaxel. Second-line
treatment with 75 mg/d
erlotinib (Tarceva)
given for 7 mo. 0.75 ng/
kg mistletoe lectin given
twice weekly
45 mg/kg given
twice a week
After a treatment for 7 mo, a nearly
complete remission (CR) of the primary
tumor and CR of all metastases was
established. The quality of life was
excellent and the patient was able to
work 100%
Table 3. (continued)

8 Integrative Cancer Therapies
The QoL improvement effects of MGN-3 were studied
by Hajto et al.58 A total of 35 patients with various malig-
nancies were administered a combination of mistletoe lectin
and MGN-3 as a complementary therapy for a minimum of
6 months during or after conventional cancer treatment.
Patients responded to a custom binary-response question-
naire with 8 questions regarding various aspects of their
QoL after treatment, including pain, anxiety, physical activ-
ity, appetite, and sleep, reporting a subjective improvement
of physical activity and decrease in side effects as the most
important benefits of the complementary therapy.58
Randomized Controlled Studies. The QoL improvement
effects of MGN-3 were previously studied in a large RCT
with 205 progressive cancer patients in late stages (III-IV)
of various malignancies.49 Checking patient QoL by obser-
vation and enquiry during the study using a custom grading
scale, Takahara and Sano49 reported that, patients who
received MGN-3 plus standard complementary and alterna-
tive therapy (CAT) achieved a higher survival rate (54.2%
vs 35.8%) and a better appetite than the control group who
received only standard CAT. There was no clear difference
between groups in terms of percentage changes in increas-
ing and decreasing NK activity, but the MGN-3 + CAT
group had a higher percentage of patients with unchanged
NK activity compared with the CAT only group.49 It was
unclear whether this study was sufficiently blinded.
The RCT by Bang et al52 can be regarded as the first
clinical evidence for the antitumor efficacy of MGN-3. The
participants of this 3-year RCT consisted of 68 patients with
liver cancers of stage I or II. A higher survival rate after the
second year (35% vs 6.7%) and lower recurrence of the dis-
ease (31.6% vs 46.7%) for liver cancer patients taking
MGN-3, compared with the controls, were the results of
MGN-3 applied in conjunction with conventional cancer
treatment in 38 patients.52 Thirty patients receiving only
conventional therapies were assigned as controls. Significant
decreases in the tumor marker level (α-fetoprotein [AFP]),
and tumor volumes, as compared with baseline, were also
observed in the MGN-3 group whereas the control group
Table 4. Characteristics of the Included Nonrandomized Clinical Studies.
No. Study N Cancer Type Duration MGN-3 Dosage
Conventional and
Adjunct Treatment Outcome Measurement Outcomes
1 Ghoneum
and Brown
(1999)48
32 Prostate, breast, multiple
myeloma, leukemia
2 wk
Follow-up
to 4 y
Orally at 3 g/d Most patients went
through conventional
treatment before
study
NK cells activity; NK
granularity; in vivo T
and B cells proliferation;
tumor-associated
antigens (TAA)
Increased in NK cells
activity (10×); NK cell
granularity and binding
capacity; T and B cells
proliferation. Improved
TAA measurements in
selected patients. Follow-up
results of 4 patients were
reported
2 Tsunekawa
(2004)50
16 Various malignancies 6 mo Orally at 3 g/d Patients went through
surgery, irradiation
therapy, and/
or chemotherapy
treatment before
study
Body height and weight,
leukocyte count and
subsets, NK cell
activity, tumor markers,
adverse reactions, and
interruptions
No subjective or objective
adverse effects.
Improvement in leukocyte
count and subsets,
increased and normalized
NK cell activity after
treatment
3 Lissoni et al
(2008)51
22 Various malignancies 2 mo Orally at 2 g/d
1st mo, and 1
g/d 2nd mo
Only supportive care
for pain, vomit,
nausea, and neoplastic
cachexia
Total lymphocytes, T
lymphocytes (CD3+,
CD4+, CD8+), T helper
(Th), T regulatory
(Treg), NK cells
Non–statistically significant
increase in the mean
number of Th cells and
decrease in Treg cell.
Th/Treg mean ratio
significantly enhanced
4 Golombick et
al (2016)57
20 Early B-cell lymphoid
malignancies
(monoclonal
gammopathy of
undetermined
significance [MGUS],
smoldering multiple
myeloma [SMM],
chronic lymphocytic
leukemia [CLL])
6 mo Orally at 2 g/d 6 g/d of curcumin FBC, paraprotein, free
light chains/ratio,
C-reactive protein
(CRP) erythrocyte
sedimentation
rate (ESR) rate, B2
microglobulin, sIgGs,
and surface leukocyte
markers
Increased neutrophil count
in 80% of MGUS/SMM
patients. Reduction in
raised ESR in 40% of the
MGUS/SMM patients
5 Hajto et al
(2016)58
35 Various malignancies
(mostly stage II-IV)
6 mo Orally between
12 and 45 mg/
kg twice a
week
Conventional oncologic
therapy
0.5-1.0 ng/kg mistletoe
lectin given twice a
week
Quality of life
questionnaire (pain,
anxiety, physical
activity, appetite,
sleep, digestion, side
effect, self-perceived
improvement)
Improvement of physical
activity and decrease of side
effects during conventional
oncotherapy

Ooi et al 9
showed no significant changes in either AFP or tumor
volume.52
MGN-3 was shown to reduce chemotherapy-induced
side effects among breast cancer patients who were under-
going 6 cycles of chemotherapy in another RCT with 50
patients.54 MGN-3 was given to 25 patients 1 week before
and 1 week after each cycle of chemotherapy, with the con-
trol group receiving only chemotherapy. Side effects were
assessed by a custom questionnaire given to patients at the
start of each cycle. Significant reductions in tiredness,
increased appetite, no anti-emetic needs, and reduced hair
loss compared with the control group were reported.54
In cervical cancer patients undergoing chemoradiother-
apy, MGN-3 was shown to be better than placebo in reduc-
ing the diarrheal side effect in a clinical trial reported by
Itoh et al., using a custom symptom scoring system.55
Adverse events were graded by the National Cancer Institute
scale (Common Terminology Criteria for Adverse Events
[CTCAE] v3.0). Only 2 patients in the MGN-3 group devel-
oped grade 2 (moderate) events during chemotherapy, with
the control group tending to develop adverse events of
higher grades than did the MGN-3 group.55 Patients taking
MGN-3 also showed less decrease in WBC count. However,
the results from this pilot trial with only 20 patients were
not significant due to the lack of statistical power.55
For patients with chronic fatigue syndrome (CFS) due to
cancer or cancer treatment, MGN-3 plus Oncothermia was
shown to be able to reduce the CFS symptoms in an RCT
with 50 CFS patients diagnosed with various malignan-
cies.56 The 25 patients who received 3 g/d of MGN-3 and
Oncothermia once a week had significantly lower mean
scores of Chalder Fatigue Questionnaire (CFQ) compared
Table 5. Characteristics of the Included Randomized Controlled Clinical Studies.
No. Study No. of Patients Cancer Type Duration MGN-3 Dosage
Conventional and
Adjunct Treatment Outcome Measurement Outcomes
1 Takahara and Sano
(2004) 49
205 (MGN-3: 96,
Control: 109)
Various
malignancies
18 mo Orally at 3 g/d Complementary and
alternative therapy and
anticancer drugs
NK cells activity,
survival rate; custom
quality of life scoring
on pain, malaise,
nausea, and appetite
MGN-3 group achieved
higher survival rate
and better appetite
than control group
2 Bang et al (2010)52 68 (MGN-3: 38,
Control: 30)
Hepatocellular
carcinoma (stages
I and II)
3 y Orally at 1
g/d for 12
mo during
treatment
Transarterial oily
chemoembolization
(TOCE) or TOCE and
percutaneous ethanol
injection treatment
(PEIT)
Overall response
to treatment,
α-fetoprotein (AFP)
levels, tumor volume,
recurrence, and
survival
MGN-3 group showed
lower recurrence,
higher survival
after 2nd year, and
significantly lower
AFP change compared
with control
3 Cholujova et al
(2013)53
48 (MGN-3: 32,
Placebo: 16)
Multiple myeloma 3 mo Orally at 2 g/d Alternating courses
of chemotherapy:
alkylating agents,
anthracyclines, and
glucocorticoids
Immunophenotypic
analysis; NK cells
activity; and cytokine
profiles
Increased NK activity,
myeloid DCs level,
and augmented
concentrations of Th
cell type 1-related
cytokines in MGN-3
group compared with
placebo group
4 Masood et al
(2013)54
50 (MGN-3: 25,
Control: 25)
Breast cancer 6 mo Orally at 3 g/d
1 wk before
and 1 wk
after each
chemotherapy
cycle
6 cycles of
chemotherapy
Chemotherapy induced
side effects (tiredness,
anorexia, vomiting,
and hair loss)
MGN-3 group
experienced significant
reduction in tiredness;
increased appetite; no
antiemetic needs; and
less hair fall compared
with control group
5 Itoh et al (2015)55 20 (MGN-3: 10,
Placebo: 10)
Cervical cancer 3 wk Orally at 3
g/d during
radiation
therapy
Radiation therapy:
combination of
external-beam
radiation therapy and
brachytherapy
Chemotherapy: cisplatin
and 5-fluorouracil
Gastrointestinal
side effects of
chemoradiotherapy
(diarrhea, nausea,
vomiting, loss of
appetite, safety);
WBC count; NK cell
activity
MGN-3 group showed
less diarrhea, less
decrease in WBC
count & less adverse
events, but results
were not significant
due to lack of
statistical power
6 Petrovics et al
(2016)56
50 (MGN-3: 25,
Control: 25)
Different
malignancies with
chronic fatigue
syndrome
6 mo Orally at 3 g/d
for 24 wk
Oncothermia for MGN-
3 group only
Chemo- or radiotherapy
as routine care
Quality of life score
(EORTC QLQ-C3),
pain score (visual
analogue scale [VAS]),
body pH level, blood
abnormalities, ECG,
blood test, fatigue
scale (Chalder Fatigue
Questionnaire
[CFQ])
MGN-3 group showed
changes in body pH
level to be less acidic.
Average of CFQ
score was significantly
reduced in MGN-3
group compared with
no change in control
group

10 Integrative Cancer Therapies
with baseline after 6 months of treatment. No significant
change in mean CFQ scores was recorded in the control
group who received only conventional chemo or radiother-
apy treatment.56
The effects of MGN-3 on innate immunity were studied
by Cholujova et al53 in an RCT with 48 multiple myeloma
patients (MGN-3 group, 32; placebo, 16). Detailed blood
analyses were performed before and during the 3 months of
treatment. Significant increase in NK activity, myeloid den-
dritic cell level, and augmented concentrations of Th cell
type 1-related cytokines were observed in the MGN-3
group. No significant change in the placebo group was
observed. Hence, MGN-3 clearly improved the innate
immunity profile of the patients compared with placebo.53
Risk of Bias Assessment. We have assessed the risk of bias of
the included RCTs using the Cochrane Risk of Bias tool.59
The results of the assessment are summarized in Figures 2
and 3. Because of insufficient information provided on ran-
domization and blinding, most included RCTs have unclear
risk in at least one or more items in selection bias, perfor-
mance bias, and detection bias. Only the study by Itoh
et al.55 is considered low risk in these items. Notwithstand-
ing, this study has a high risk of attrition bias due to a high
percentage of participants being excluded from assessment
(30%).55 The risks of attrition bias and reporting bias are
low in most other studies except the study by Masood el
al,54 which has unclear risk of bias across all items of assess-
ment due to insufficient detail in published information. We
assess the study by Takahara and Sano49 to have a high risk
in other bias. It was conducted by a commercial hospital
specialized in CAT for cancer patients, thus the risk of bias
cannot be excluded due to conflict of interest. With industry
influence being a potential source of other bias, only the
study by Petrovics el al56 provided disclosure on funding
and clarified the roles of industry partners in the study,
which the other studies did not.
Discussion
Current evidence supports MGN-3 to be a BRM. MGN-3 is
an evidence based and standardized arabinoxylan concen-
trate from plant origin which, similar to bacterial pathogen
associated molecular pattern molecules, can stimulate the
body’s natural immune system to protect against cancer
growth.46 The effect of MGN-3 in upregulating the cyto-
toxic activities of NK cells, by multiple-fold, has been
most prominently demonstrated.34,48-50,53 The anticancer
effect of NK cells is the subject of intense current research
and NK cell immunotherapy is being touted as the future of
cancer immunotherapy.4 Effectiveness of NK activity has
been associated with good prognosis in patients with meta-
static cancers.60,61 This may explain the life-prolongation
effect of MGN-3 as reported in a number of clinical stud-
ies49,52 and case reports.42-44 However, MGN-3 treatment
does not increase the absolute NK cell counts as noted in
clinical studies,51,57 which is a limitation. Cancer patients
with low NK cell counts (<0.15 × 109/L) tend to have lower
survival rates,62,63 indicating that lower basic level of natu-
ral antitumor activity can reduce the efficacy of a BRM.
While they may benefit from the upregulated NK activity
with MGN-3 treatment to a certain extent,49 combining NK
cellular therapy64 with MGN-3 may further improve prog-
nosis in these patients; an approach that warrant future
clinical investigation.34
Other immunomodulatory effects of MGN-3 include the
following: increase susceptibility of cancer cells to undergo
apoptosis mediated by CD95 death receptors28; influence
plasma cytokine production (upregulated TNF-α and IL-12,
while downregulating IL-10)37; enhance the activity of anti-
oxidant enzymes38; improve T and B cell proliferation48;
improve Th cell concentration,51,53 downregulate Treg
cells51; and activate dendritic cells.13,22,53 These effects have
been presented in depth by Ghoneum65 in a recent review,
supporting the use of MGN-3 as an effective BRM in cancer
therapy.
MGN-3 has been tested in clinical trials as an adjunct
therapy during conventional chemo- and radiotherapy with
effects that include (1) improvement of immunoprofile,53,55
Figure 2. Risk of bias summary: Review authors’ judgements
about each risk of bias item for each included study.

Ooi et al 11
(2) reduction of side effects (diarrhea, nausea, pain, tired-
ness, anorexia, and vomiting),52,54-56,58 and (3) improvement
in treatment outcomes.52 Outcome improvement and reduc-
tion of side effects have been mostly attributed to an
improved balance of the innate immune system. However,
MGN-3 has also been shown to work synergistically with
daunorubin31 and paclitaxel33,40 in preclinical studies, as
well as transarterial oily chemoembolization (TOCE) and
percutaneous ethanol injection treatment (PEIT) for liver
cancer treatment in a clinical trial,52 by sensitizing the can-
cer cells to these agents. More research is needed to explore
such synergistic effects with other chemotherapeutic agents
and radiation therapy to fully explore the potential of
MGN-3 as a combination therapy in conventional cancer
treatment.
As a follow-up therapy after conventional cancer treat-
ment, MGN-3 has demonstrated effects in restoring weak-
ened immunoprofile,48-51 improving QoL and survival rate
of late-stage cancer patients,49 as well as reducing recur-
rence.52 Such results are consistent with the clinical experi-
ences reported in the published case reports.42-47 As such,
MGN-3 may also be considered as part of the follow-up
care after conventional cancer treatment.
No adverse reaction was reported in studies that explic-
itly monitored potential MGN-3 induced adverse effects in
vivo37 and in a clinical study.50 No adverse event due to
MGN-3 was reported in any of the included clinical trials or
clinical case reports. Furthermore, the safety MGN-3 has
been studied in a series of animal studies. The median lethal
dose (LD50) of MGN-3 is more than 36 g/kg, and the “no
observed adverse effect level (NOAEL)" is 200 mg/kg/d or
higher.66 Therefore, typical MGN-3 dosages of 3 to 6 g/d or
45 mg/kg BW/d are extremely safe.
At present, there is no study on the pharmacokinetics of
MGN-3 and the achievable level of MGN-3 in serum is
unknown (personal email communication with Dr Mamdooh
Ghoneum at Charles Drew University of Medicine and
Science on August 4, 2017). Since concentrations of
MGN-3 used in some of in vitro studies were very high
(500-1000 μg/mL),28,29,31,33 it is unclear whether these con-
centrations can be of clinical relevance. Although the
MGN-3 dosages (5-50 mg/kg/BW) used for in vivo stud-
ies34,35,37-41 were more closely matched to the typical dosage
used in human studies, without understanding of the phar-
macokinetics of MGN-3, questions remain whether the
higher bioavailability via intraperitoneal injection in some
animal studies36-41 can be applicable to humans.
The clinical research on MGN-3 is still at its early stage
with only a small number of RCTs available in the litera-
ture. Most of them are small pilot trials with limited partici-
pants (N < 100) and short duration (<=6 months). At the
moment only one RCT is available to support clinical evi-
dence.52 The other RCT that has adequate size (N = 205)
and duration (18 months)49 suffers from methodological
limitations including inadequate blinding, no placebo con-
trol, and potential risk of bias due to conflict of interest.
Hence, large, well-designed, long-term placebo-controlled
RCTs are needed to further evaluate the effects of MGN-3
as a complementary therapy to support conventional cancer
treatment.
Conclusion
Current evidence from preclinical studies, clinical case
reports, and small clinical trials suggests that MGN-3 can
be an effective BRM to complement the conventional can-
cer treatment through upregulating the patient’s immune
system, especially in boosting the NK cell activity. MGN-3
appears safe in its application with no adverse event reported
to date. It may be used as a complementary immune therapy
to reduce side effects, improve treatment outcomes, and
enhance long-term survival rate. The combination of
MGN-3 with new biological targeting treatments may open
new perspectives in the tumor therapy. Nevertheless, we
call for additional study into the pharmacokinetics of MGN-
3, as well as more well-designed RCTs to confirm its
Figure 3. Risk of bias graph: Review authors’ judgements about each risk of bias item presented as percentages across all included
studies.

12 Integrative Cancer Therapies
efficacies and strengthen the evidence to support its clinical
application.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
References
1. Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer
incidence and mortality rates and trends—an update. Cancer
Epidemiol Biomarkers Prev. 2016;25:16-27.
2. Sudhakar A. History of cancer, ancient and modern treatment
methods. J Cancer Sci Ther. 2010;1:1-4.
3. Qiao J, Liu Z, Fu YX. Adapting conventional cancer treat-
ment for immunotherapy. J Mol Med (Berl). 2016;94:
489-495.
4. Kuroki M, Miyamoto S, Morisaki T, et al. Biological
response modifiers used in cancer biotherapy. Anticancer
Res. 2012;32:2229-2233.
5. Zugazagoitia J, Guedes C, Ponce S, Ferrer I, Molina-Pinelo
S, Paz-Ares L. Current challenges in cancer treatment. Clin
Ther. 2016;38:1551-1566.
6. Biemar F, Foti M. Global progress against cancer-challenges
and opportunities. Cancer Biol Med. 2013;10:183-186.
7. BioBran.org. Biobran MGN-3—an overview. https://biobran.
org/overview. Accessed May 18, 2017.
8. Miura T, Chiba M, Miyazaki Y, Kato Y, Maeda H. Chemical
structure of the component involved in immunoregulation.
In: BioBran/MGN-3 (Rice Bran Arabinoxylan Coumpound):
Basic and Clinical Application to Integrative Medicine. 2nd ed.
Tokyo, Japan: BioBran Research Foundation; 2013:14-22.
9. Paterson A. Therapeutic properties of biobran MGN-3.
http://www.positivehealth.com/article/nutraceuticals/thera-
peutic-properties-of-biobran-mgn-3. Posit Heal. Published
September 2002. Accessed September 19, 2017.
10. Tazawa K. BioBran/MGN-3 (Rice Bran Arabinoxylan
Compound): Basic and Clinical Application to Integrative
Medicine. 2nd ed. Tokyo, Japan: BioBran Research
Foundation; 2013.
11. Ghoneum M, Hamilton J, Gollapudi S. Modified arabinox-
ylan rice bran (MGN-3/biobran), potentiates chemotherapy-
induced apoptosis in human breast cancer cells. J Nutr.
2004;134:3541S.
12. Badr El-Din N, Noaman E, Ghoneum A, Ghoneum M. Rice
bran supplement (MGN-3/Biobran) suppresses tumor growth
via modulating cytokine production and increasing apop-
totic level in ehrlich carcinoma-bearing mice. Clin Immunol.
2007;123(suppl):S117.
13. Cholujova D, Jakubikova J, Sulikova M, et al. The effect of
MGN-3 arabinoxylan on natural killer and dendritic cells in
multiple myeloma patients. Haematologica. 2011;96(suppl
1):S117-S118.
14. Badr El-Din NK, Fattah SMA, Pan D, Tolentino L, Ghoneum
M. Chemopreventive activity of BioBran/MGN-3, an ara-
binoxylan from rice bran, against chemical induction of
gastric dysplasia and adenocarcinoma in rats. Cancer Res.
2014;74(19 Suppl):Abstract 234.
15. Badr El-Din NK, Ali DA, Alaa El-Dein M, Ghoneum M.
Biobran/MGN-3, arabinoxylan from rice bran, sensitizes
breast adenocarcinoma tumor cells to paclitaxol in mice.
Cancer Res. 2015;75(15 Suppl):Abstract 5312.
16. Giese S, Sabell GR, Coussons-Read M. Impact of ingestion of
rice bran and shitake mushroom extract on lymphocyte func-
tion and cytokine production in healthy rats. J Diet Suppl.
2008;5:47-61.
17. Ghoneum M, Badr El-Din NK, Fattah SMA, Tolentino L.
Arabinoxylan rice bran (MGN-3/Biobran) provides protec-
tion against whole-body γ-irradiation in mice via restoration
of hematopoietic tissues. J Radiat Res. 2013;54:419-429.
18. Ghoneum M, Jewett A. Production of tumor necrosis factor-
alpha and interferon-gamma from human peripheral blood
lymphocytes by MGN-3, a modified arabinoxylan from rice
bran, and its synergy with interleukin-2 in vitro. Cancer
Detect Prev. 2000;24:314-324.
19. Ghoneum M, Agrawal S. MGN-3/Biobran enhances genera-
tion of cytotoxic CD8+ T cells via upregulation of DEC-205
expression on dendritic cells. Int J Immunopathol Pharmacol.
2014;27:523-530.
20. Ghoneum M, Agrawal S. Activation of human monocyte-
derived dendritic cells in vitro by the biological response
modifier arabinoxylan rice bran (MGN-3/Biobran). Int J
Immunopathol Pharmacol. 2011;24:941-948.
21. Ghoneum M, Abedi S. Enhancement of natural killer cell
activity of aged mice by modified arabinoxylan rice bran
(MGN-3/Biobran). J Pharm Pharmacol. 2004;56:1581-1588.
22. Cholujova D, Jakubikova J, Sedlak J. BioBran-augmented
maturation of human monocyte-derived dendritic cells.
Neoplasma. 2009;56:89-95.
23. Hajtó T, Adámy A, Langmár Z, et al. Enhanced effectiveness of
conventional oncotherapy with plant immunomodulators: over-
view of recent advances. Adv Med Plant Res. 2013;1:56-65.
24. Tan BL, Norhaizan ME. Scientific evidence of rice by-prod-
ucts for cancer prevention: chemopreventive properties of
waste products from rice milling on carcinogenesis in vitro
and in vivo. Biomed Res Int. 2017;2017:1-18.
25. Zhang S, Li W, Smith CJ, Musa H. Cereal-derived arabinox-
ylans as biological response modifiers: extraction, molecular
features, and immune-stimulating properties. Crit Rev Food
Sci Nutr. 2015;55:1035-1052.
26. Meshitsuka K. A case of stage IV hepatocellular carcinoma
treated by KM900, Biobran, and psychotherapy has presented
significant good results. Pers Med Universe (Japanese Ed.)
2016;1:46-48.
27. Ghoneum M, Tachiki K, Ueyama K, Makinodan T, Makhijani
N, Yamaguchi D. Natural biological response modifier
(MGN-3) shown to be effective against tumor cell growth.
Paper presented at the 8th International Congress on Anti-
Aging & Biomedical Technologies; December 14, 2000; Las
Vegas, NV.
28. Ghoneum M, Gollapudi S. Modified arabinoxylan rice bran
(MGN-3/Biobran) sensitizes human T cell leukemia cells

Ooi et al 13
to death receptor (CD95)-induced apoptosis. Cancer Lett.
2003;201:41-49.
29. Ghoneum M, Gollapudi S. Modified arabinoxylan rice
bran (MGN-3/Biobran) enhances yeast-induced apopto-
sis in human breast cancer cells in vitro. Anticancer Res.
2005;25:859-870.
30. Ghoneum M, Gollapudi S. Synergistic role of arabinoxylan
rice bran (MGN-3/Biobran) in S. cerevisiae-induced apopto-
sis of monolayer breast cancer MCF-7 cells. Anticancer Res.
2005;25:4187-4196.
31. Gollapudi S, Ghoneum M. MGN-3/Biobran, modified arabi-
noxylan from rice bran, sensitizes human breast cancer cells
to chemotherapeutic agent, daunorubicin. Cancer Detect
Prev. 2008;32:1-6.
32. Ghoneum M, Gollapudi S. Synergistic apoptotic effect of
arabinoxylan rice bran (MGN-3/Biobran) and curcumin (tur-
meric) on human multiple myeloma cell line U266 in vitro.
Neoplasma. 2011;58:118-123.
33. Ghoneum M, Badr El-Din NK, Ali DA, El-Dein MA.
Modified arabinoxylan from rice bran, MGN-3/Biobran, sen-
sitizes metastatic breast cancer cells to paclitaxel in Vitro.
Anticancer Res. 2014;34:81-88.
34. Pérez-Martínez A, Valentín J, Fernández L, et al. Arabinoxylan
rice bran (MGN-3/Biobran) enhances natural killer cell-medi-
ated cytotoxicity against neuroblastoma invitro and invivo.
Cytotherapy. 2015;17:601-612.
35. Jacoby HI, Wnorowski G, Sakata K, Maeda H. The effect of
MGN-3 on cisplatin and doxorubicin induced toxicity in the
rat. J Nutraceut Funct Med Foods. 2001;3:3-11.
36. Endo Y, Kanbayashi H. Modified rice bran beneficial for
weight loss of mice as a major and acute adverse effect of
cisplatin. Pharmacol Toxicol. 2003;92:300-303.
37. Badr El-Din NK, Noaman E, Ghoneum M. In vivo tumor
inhibitory effects of nutritional rice bran supplement MGN-3/
Biobran on ehrlich carcinoma-bearing mice. Nutr Cancer.
2008;60:235-244.
38. Noaman E, Badr El-Din NK, Bibars MA, Mossallam AAA,
Ghoneum M. Antioxidant potential by arabinoxylan rice bran,
MGN-3/biobran, represents a mechanism for its oncostatic
effect against murine solid Ehrlich carcinoma. Cancer Lett.
2008;268:348-359.
39. Badr El-Din NK, Fattah SMA, Pan D, Tolentino L, Ghoneum
M. Chemopreventive activity of MGN-3/Biobran against
chemical induction of glandular stomach carcinogenesis in
rats and its apoptotic effect in gastric cancer cells. Integr
Cancer Ther. 2016;15:NP26-NP34.
40. Badr El-Din NK, Ali DA, Alaa El-Dein M, Ghoneum M.
Enhancing the apoptotic effect of a low dose of paclitaxel
on tumor cells in mice by arabinoxylan rice bran (MGN-3/
Biobran). Nutr Cancer. 2016;68:1010-1020.
41. Badr El-Din NK, Ali DA, Othman R, Ghoneum M. Prevention of
hepatocarcinogenesis in rats by arabinoxylan rice bran, MGN-3/
Biobran. Cancer Res. 2016;76(14 Suppl):Abstract 5259.
42. Kawai T. One case of a patient with umbilical metastasis
of recurrent cancer (Sister Mary Joseph’s Nodule, SMJN)
who has survived for a long time under immunomodula-
tory supplement therapy. Clin Pharmacol Ther. 2004;14:
281-288.
43. Kaketani K. A case where an immunomodulatory food was
effective in conservative therapy for progressive terminal
pancreatic cancer. Clin Pharmacol Ther. 2004;14:273-279.
44. Okamura Y. The clinical significance of modified arabinox-
ylan from rice bran (BioBran/MGN-3) in immunotherapy for
cancer. Clin Pharmacol Ther. 2004;14:289-294.
45. Markus J, Miller A, Smith M, Orengo I. Metastatic heman-
giopericytoma of the skin treated with wide local excision and
MGN-3. Dermatol Surg. 2006;32:145-147.
46. Hajto T, Baranyai L, Kirsch A, Kuzma M, Perjési P. Can a
synergistic activation of pattern recognition receptors by plant
immunomodulators enhance the effect of oncologic therapy?
Case Report of a patient with uterus and ovary sarcoma. Clin
Case Reports Rev. 2015;1(10):235-238.
47. Hajto T, Horváth A, Baranyai L, Kuzma M, Perjési P. Can
the EGFR inhibitors increase the immunomodulatory effects
of standardized plant extracts (mistletoe lectin and arabonox-
ylan) with clinical benefit? Case report of a patient with lung
adenocarcinoma. Clin Case Rep Rev. 2016;2:456-459.
48. Ghoneum M, Brown J. NK Immunorestoration and cancer
patients by BioBran/MGN-3, a modified aracbynoxylan rice
bran (study of 32 patients followed for up to 4 years). In: RM
Klatz & R Goldman, eds. Anti-Aging Medical Therapeutics,
Vol III. Marina del Rey, CA: Health Quest; 1999:217-226.
49. Takahara K, Sano K. Life prolongation and QOL improve-
ment effect of modified arabinoxylan from rice bran
(BioBran/MGN-3) for progressive cancer. Clin Pharmacol
Ther. 2004;14:267-271.
50. Tsunekawa H. Effect of long-term administration of immuno-
modulatory food on cancer patients completing conventional
treatments. Clin Pharmacol Ther. 2004;14:295-302.
51. Lissoni P, Messina G, Brivio F, et al. Modulation of the
anticancer immunity by natural agents: inhibition of T regu-
latory lymphocyte generation by arabinoxylan in patients
with locally limited or metastatic solid tumors. Cancer Ther.
2008;6:1011-1016.
52. Bang MH, Van Riep T, Thinh NT, et al. Arabinoxylan rice
bran (MGN-3) enhances the effects of interventional thera-
pies for the treatment of hepatocellular carcinoma: a three-
year randomized clinical trial. Anticancer Res. 2010;30:
5145-5151.
53. Cholujova D, Jakubikova J, Czako B, et al. MGN-3 arabinox-
ylan rice bran modulates innate immunity in multiple myeloma
patients. Cancer Immunol Immunother. 2013;62:437-445.
54. Masood AI, Sheikh R, Anwer RA. “Biobran MGN-3”; effect
of reducing side effects of chemotherapy in breast cancer
patients. Prof Med J. 2013;20:13-16.
55. Itoh Y, Mizuno M, Ikeda M, et al. A randomized, double-
blind pilot trial of hydrolyzed rice bran versus placebo for
radioprotective effect on acute gastroenteritis secondary to
chemoradiotherapy in patients with cervical cancer. Evid
Based Complement Alternat Med. 2015;2015:947390.
56. Petrovics G, Szigeti G, Hamvas S, Máté Á, Betlehem J, Hegyi
G. Controlled pilot study for cancer patients suffering from
chronic fatigue syndrome due to chemotherapy treated with
BioBran (MGN-3-Arabinoxylan) and targeted radiofrequency
heat therapy. Eur J Integr Med. 2016;8:29-35.
57. Golombick T, Diamond TH, Manoharan A, Ramakrishna R.
Addition of rice bran arabinoxylan to curcumin therapy may

14 Integrative Cancer Therapies
be of benefit to patients with early-stage B-cell lymphoid
malignancies (monoclonal gammopathy of undetermined sig-
nificance, smoldering multiple myeloma, or stage 0/1 chronic
lymphocytic leukemia). Integr Cancer Ther. 2016;15:183-189.
58. Hajto T, Horvath A. Improvement of quality of life in tumor
patients after an immunomodulatory treatment with standard-
ized mistletoe lectin and arabinoxylan plant extracts. Int J
Neurorehabil. 2016;3(2):2-4.
59. Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane
Collaboration’s tool for assessing risk of bias in randomised
trials. BMJ. 2011;343:d5928.
60. Takeuchi H, Maehara Y, Tokunaga E, Koga T, Kakeji Y,
Sugimachi K. Prognostic significance of natural killer cell
activity in patients with gastric carcinoma: a multivariate
analysis. Am J Gastroenterol. 2001;96:574-578.
61. Pasero C, Gravis G, Granjeaud S, et al. Highly effective NK
cells are associated with good prognosis in patients with met-
astatic prostate cancer. Oncotarget. 2015;6:14360-14373.
62. Kim JK, Chung JS, Shin HJ, et al. Influence of NK cell count
on the survival of patients with diffuse large B-cell lymphoma
treated with R-CHOP. Blood Res. 2014;49:162-169.
63. He L, Zhu H-Y, Qin S-C, et al. Low natural killer (NK)
cell counts in peripheral blood adversely affect clinical out-
come of patients with follicular lymphoma. Blood Cancer J.
2016;6:e457.
64. Berrien-Elliott MM, Romee R, Fehniger TA. Improving
natural killer cell cancer immunotherapy. Curr Opin Organ
Transplant. 2015;20(6):671-680.
65. Ghoneum M. From bench to bedside: The growing use of
arabinoxylan rice bran (MGN-3/Biobran) in cancer immuno-
therapy. Austin Immunol. 2016;1(2).
66. The safety of Biobran/MGN-3. In: BioBran/MGN-3 (Rice
Bran Arabinoxylan Coumpound): Basic and Clinical
Application to Integrative Medicine. 2nd ed. Tokyo, Japan:
BioBran Research Foundation; 2013:9-13.