An Exploratory Study on the Anti-inflammatory Effects of Fucoidan in Relation to Quality of Life in Advanced Cancer Patients

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DOI: 10.1177/1534735417692097
Cite this publication
Abstract
Background: Conventional anticancer therapies still cause difficulties with selective eradication and accompanying side effects that reduce patients' quality of life (QOL). Fucoidan is extracted from seaweeds and has already exhibited broad bioactivities, including anticancer and anti-inflammatory properties, in basic studies. It is expected to enhance therapeutic efficacy and minimize side effects in cancer patients; however, despite its potential benefits, there are very few clinical trials using fucoidans. Therefore, we performed an exploratory clinical study for advanced cancer patients to examine the efficacy of fucoidans, especially focusing on inflammation in relation to QOL scores. Methods: We conducted a prospective, open-label clinical study for advanced cancer patients using fucoidans via oral administration; 20 advanced cancer patients with metastases were recruited and were given 400 mL/d fucoidan (10 mg/mL) for at least 4 weeks. Inflammatory biomarkers, including high-sensitivity C-reactive protein and various cytokines, and QOL scores were monitored before treatment, after 2 weeks, and after 4 weeks of fucoidan ingestion. Results: The main proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) were significantly reduced after 2 weeks of fucoidan ingestion. QOL scores, including fatigue, stayed almost stable without significant changes during the study period. The univariate and multivariate analyses revealed that the responsiveness of IL-1β was a significant independent prognostic factor. Conclusion: This is the first study providing evidence of the anti-inflammatory effects of fucoidans for advanced cancer patients. In future studies, larger blinded, controlled trials are required to establish the efficacy of fucoidan as supportive care for cancer patients, especially those undergoing chemotherapy.
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Research Article
692097ICTXXX10.1177/1534735417692097Integrative Cancer TherapiesTakahashi et al
research-article2017
An Exploratory Study on the
Anti-inflammatory Effects of Fucoidan in
Relation to Quality of Life in Advanced
Cancer Patients
Hidenori Takahashi, MD1,2,3, Mitsuhiko Kawaguchi, MD, PhD4,
Kunihiro Kitamura, MD, PhD5, Seiji Narumiya, MD, PhD6,
Munenori Kawamura, MD, PhD7, Isamu Tengan, MD3, Shinji Nishimoto, MD8,
Yasuo Hanamure, MD, PhD9, Yasuo Majima, MD, PhD10,
Shuichi Tsubura, DDS, PhD11, Kiichiro Teruya, PhD12,
and Sanetaka Shirahata, PhD12
Abstract
Background. Conventional anticancer therapies still cause difficulties with selective eradication and accompanying side effects
that reduce patients’ quality of life (QOL). Fucoidan is extracted from seaweeds and has already exhibited broad bioactivities,
including anticancer and anti-inflammatory properties, in basic studies. It is expected to enhance therapeutic efficacy and
minimize side effects in cancer patients; however, despite its potential benefits, there are very few clinical trials using fucoidans.
Therefore, we performed an exploratory clinical study for advanced cancer patients to examine the efficacy of fucoidans,
especially focusing on inflammation in relation to QOL scores. Methods. We conducted a prospective, open-label clinical
study for advanced cancer patients using fucoidans via oral administration; 20 advanced cancer patients with metastases
were recruited and were given 400 mL/d fucoidan (10 mg/mL) for at least 4 weeks. Inflammatory biomarkers, including high-
sensitivity C-reactive protein and various cytokines, and QOL scores were monitored before treatment, after 2 weeks, and
after 4 weeks of fucoidan ingestion. Results. The main proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, and
tumor necrosis factor-α (TNF-α) were significantly reduced after 2 weeks of fucoidan ingestion. QOL scores, including fatigue,
stayed almost stable without significant changes during the study period. The univariate and multivariate analyses revealed that
the responsiveness of IL-1β was a significant independent prognostic factor. Conclusion. This is the first study providing evidence
of the anti-inflammatory effects of fucoidans for advanced cancer patients. In future studies, larger blinded, controlled trials are
required to establish the efficacy of fucoidan as supportive care for cancer patients, especially those undergoing chemotherapy.
Keywords
fucoidan, cytokine, inflammation, cancer, QOL, IL-1β
Submitted Date: 3 October 2016; Revised Date: 26 December 2016; Acceptance Date: 7 January 2017
1University of the Ryukyus Hospital, Nakagami-gun, Okinawa, Japan
2Seren Clinic Fukuoka, Fukuoka, Japan
3Clinic Ginowan, Ginowan-shi, Okinawa, Japan
4Kawaguchi Medical Clinic, Okayama-shi, Okayama, Japan
5Kitamura Clinic, Onojo-shi, Fukuoka, Japan
6Dojima Liga Clinic, Fukushima-ku, Osaka, Japan
7Kyowa Hospital, Kobe-shi, Hyogo, Japan
8Nishimoto Clinic, Wakayama-shi, Wakayama, Japan
9Hanamure Hospital, Ichikikushikino-shi, Kagoshima, Japan
10Majima Digestive Organ Clinic, Kurume-shi, Fukuoka, Japan
11Nippon Dental University School of Life Dentistry at Niigata, Hamaura-cho, Chuo-ku, Niigata, Japan
12Kyushu University, Higashi-ku, Fukuoka, Japan
Corresponding Author:
Hidenori Takahashi, University of the Ryukyus Hospital, 207 Uehara, Nishihara-cho, Nakagami-gun, Okinawa 903-0215, Japan.
Email: bzr06263@med.u-ryukyu.ac.jp
2 Integrative Cancer Therapies
Introduction
A close association between cancer and inflammatory
responses is now well established. The idea was first postu-
lated by R. Virchow in the nineteenth century and has sub-
sequently been corroborated by a growing number of
studies.1-5 Approximately 90% to 95% of cancers are caused
by lifestyle and environmental factors such as food, smok-
ing, infectious agents, and stress. When these inflammatory
stresses persist for a long time, chronic inflammation may
appear, giving rise to tumor development and metastasis.2,3
In addition to inflammatory stresses, cancer itself induces
inflammatory reactions, which bring about symptoms such
as pain, fever, anorexia and weight loss, fatigue, and cancer
cachexia in the terminal stages. The inflammatory reactions
may also affect therapeutic efficacy.4-6 Moreover, chemo-
therapy (Cx) for advanced cancer induces inflammatory
reactions, which may result in many side effects and also
accelerate tumor growth.7 Inflammatory responses are
mediated by multiple factors, notably proinflammatory
cytokines, including interleukin-1β (IL-1β), IL-6, and
tumor necrosis factor-α (TNF-α).1-7 These proinflamma-
tory cytokines have been shown to participate in the various
stages of cancer. For example, elevated serum concentra-
tions of IL-1β were detected in cancer patients,8-10 and a
shorter life span was reported in advanced cancer patients
with high inflammatory cytokine levels.11-13
As mentioned above, cancer and inflammatory responses
are closely associated, suggesting the possibility of thera-
peutic interventions with anti-inflammatory agents.6,7,14-16
Steroids are the standard anti-inflammatory therapy for
symptoms, including nausea and fatigue, in patients with
advanced cancer.17 However, steroidal and nonsteroidal
anti-inflammatory drugs have many serious side effects
such as immunosuppression, ulceration, and organ dysfunc-
tion, especially for advanced cancer patients.18-20 Because
there is currently no way to prevent these side effects, there
is a strong demand for improved anti-inflammatory agents
in clinic, especially for patients with advanced cancer.6
One promising biomaterial, fucoidan, is mainly present in
various species of brown marine macroalgae (or seaweeds)
such as mozuku, kombu, bladderwrack, and others.21 Fucoidans
are sulfated polysaccharides having complicated chemical
structures, consisting of various combinations of fucose, uronic
acids, galactose, and xylose.21,22 Isolated fucoidans without fur-
ther treatments may present in various sizes, for example, 5100
kDa23 and 1600 kDa,24 depending on the methods of extraction
and seaweeds used. Various molecular weight derivatives, for
example, classified as low-molecular-weight fucoidan (up to 40
kDa), intermediate-molecular-weight fucoidan (110-138 kDa),
and high-molecular-weight fucoidan (300-330 kDa), have been
examined for their health benefits and were reported to exhibit
broad biological activities such as anticancer, antioxidant, anti-
coagulant, anti-inflammatory, and immune-modulatory effects
in in vitro and in vivo studies.21,22,25-27 One of our previous basic
science studies revealed that fucoidan can enhance the anticancer
activity of chemotherapeutic agents (such as cisplatin, tamoxi-
fen, and paclitaxel).28 There are substantial data showing that
the low toxicity of fucoidan makes it a suitable supplemental
treatment for cancer patients along with conventional thera-
pies.29,30 Despite its potential benefits, there is little clinical data
on the effects of fucoidan; the only available study is a recent
prospective randomized clinical trial revealing that fucoidan
significantly reduces the general fatigue caused by Cx in
advanced colorectal cancer patients.31 Therefore, further
research is needed to confirm the efficacy of fucoidan in clinical
cancer management.
Here, we hypothesized that fucoidan, as a supportive
care agent, could alleviate inflammatory conditions and
improve the quality of life (QOL) in advanced cancer
patients. In the present study, we conducted an exploratory
prospective clinical study to monitor various biomarkers,
including proinflammatory cytokines, and QOL scores in
advanced cancer patients receiving fucoidan.
Methods
This study was conducted as a prospective, open-label, sin-
gle-arm clinical study under institutional ethical committee
approval. Consecutive cancer patients were recruited from 4
medical clinics in Japan from January 2014 to February 2015.
Written informed consent was obtained from all patients who
agreed to receive 400 mL/d of fucoidan (10 mg/mL; trade
name: Power Fucoidan, Daiichi Sangyo, Co Ltd, Osaka,
Japan) for at least 4 weeks. As shown in Figure 1 and Table 1,
the total number of 20 patients who met the following inclu-
sion criteria were eligible for this study: (1) clinically diag-
nosed with inoperable metastatic cancer; (2) age >20 years,
(3) ambulatory as an outpatient with normal food intake for at
least 4 weeks during the study, and (4) without serious dys-
function of vital organs. Because there was no control group
in this exploratory study, we considered setting the baseline
for each patient’s status before the administration of fucoi-
dan; then, these data were compared with their status at the
second week and fourth week of treatment.
The study was approved by the ethics committee of the
Low Molecular Fucoidan Research Association (Reference
Number: #20131101-1) and conducted in accordance with
the ethical standards as laid down in the 1964 Helsinki
Declaration and its later amendments or comparable ethical
standards. Written informed consent was obtained from all
participants included in this study.
Materials
The abalone glycosidase-digested fucoidan extract from the
brown seaweed Mozuku, Cladosiphon novae-caledoniae
Kylin, used in the present study, is commercially available
Takahashi et al 3
as Power Fucoidan through the Daiichi Sangyo Corporation
(Osaka, Japan). The molecular composition of Power
Fucoidan is as follows: 72% digested low-molecular-weight
fractions with less than 500 Da, and 28% nondigested frac-
tions with peak molecular weight of 800 kDa.28 Therefore,
Power Fucoidan consists mostly of a mixture of digested
and nondigested fractions of fucoidan and other minor sub-
stances.28,32 It is presented as an aqueous solution contain-
ing 10 mg/mL of low-molecular-weight fractions as the
main constituents.
Endpoints
The primary endpoints of this study were changes in inflam-
matory biomarkers, including high-sensitivity C-reactive
protein (CRP) and proinflammatory cytokines (IL-1β, IL-6,
TNF-α). Secondary endpoints were QOL scores using the
European Organization for Research and Treatment of
Cancer Quality-of-Life Questionnaire Core 30 (EORTC
QLQ-C30) and overall survival. These endponts were mon-
itored at outpatient visits using blood sampling and ques-
tionnaires before, at the second week, and at the fourth
week of fucoidan ingestion.
Blood Collection and Immunological Assessment
Peripheral blood (2 mL) was collected in a tube containing
EDTA-2K, and used for a blood count, differential leuko-
cyte counts, detecting high-sensitivity CRP levels, and flow
cytometry analysis. Another 8 mL of peripheral blood was
collected in a BD Vacutainer CPT Cell Preparation Tube
(Becton-Dickinson, CA) for the separation of mononuclear
cells to be used for cytokine measurements.
We aimed at identifying T cells (CD3+ cells), B cells
(CD20+ cells), natural killer (NK) cells, and NK subsets
(CD56+CD16, CD56+CD16+, CD56CD16+, CD56+CD16+
perforin+granzymeB+,CD56+CD16perforin+granzymeB+)
as well as subpopulations of T cells: CD4+, CD8+, naïve
CD4+ (CD4+CD45RA+ cells), memory CD4+ (CD4+CD45RA
cells), and CD8+CD28+ T cells. Therefore, mononuclear cells
were stained with a combination of monoclonal antibodies
conjugated with chromophores and analyzed using the
Navios Flow Cytometer (Beckman Coulter, FL). The follow-
ing monoclonal antibodies (Beckman Coulter) were used:
fluorescein isothiocyanate (FITC)-conjugated anti-CD8,
anti-CD20, and anti-CD25; phycoerythrin (RD1)-
conjugated anti-CD3 and anti-CD4; phycoerythrin-Texas
Red (ECD)-conjugated anti-CD3 and anti-CD45RA; phy-
coerythrin-cyanin 5.1 (PC5)-conjugated anti-CD28 and
CD16; phycoerythrin-cyanin 7 (PC7)-conjugated anti-CD45;
and allophycocyanin (APC)-conjugated anti-CD4 and anti-
CD56. In addition, the following combinations with mono-
clonal antibodies were used: (1) CD3-RD1/CD20-FITC/
CD16-PC5/CD45-PC7/CD56-APC, (2) CD4-APC/CD8-
FITC/CD45RA-ECD/CD28-PC5/CD45-PC7, and (3) CD3-
ECD/CD4-PE/CD25-FITC.
The isolated mononuclear cells (1 × 106/well) were cul-
tured for 48 hours in a 24-well culture plate coated with an
anti-CD3 monoclonal antibody. The collected culture super-
natant was stored at −80°C until cytokine measurement.
RecruitedCancer Patients: N=28
From Jan/2014toFeb/2015
Stop ingestion earlier than 4 weeks: N=5
(N=4: disease progression;N=1: withdrew by patient request)
No metastasis: N=3 (Removed from the study)
Advanced/Recurrence Stages: N=25
Continued fucoidan ingestion over 4 weeks: N=20
Figure 1. Flow diagram of patients’ treatment: 20 patients who met all the inclusion criteria were analyzed in this study.
4 Integrative Cancer Therapies
Cytokines (IL-1β, IL-2, IL-6, IL-12, IL-17, IL-23,
interferon-γ, and TNF-α) were measured using a flow
cytometer (Navios: Beckman Coulter, Miami, FL) with a
BD Cytometric Bead Array (BD CBA: Becton Dickinson).
Immunological analysis of peripheral blood was carried out
in the Institute for Health & Life Sciences (HLS, Tokyo,
Japan) using the analytical technologies patented by Tokyo
Medical and Dental University (Patent No.: JP4608704B233;
Patent No.: JP5030109B234; Patent No.: US 8,815,524B235).
Statistical Analyses
Data are presented as means ± standard error of the mean
(SEM). The significance of differences between time points
was determined using the Wilcoxon signed-rank test. The
differences between the 2 groups of categorical data were
analyzed using the Mann-Whitney U test or Pearson’s χ2
test. Survival curves were plotted using the Kaplan-Meier
method, and survival curve comparisons were conducted
using the log-rank test and multivariate analysis (Cox’s pro-
portional hazards regression model). A value of P < .05 was
considered significant. Analyses were conducted using JMP
version 11.0 (SAS Institute Japan, Tokyo, Japan).
Results
Patient Characteristics
In this study, 28 cancer patients were initially recruited in
collaboration with 4 clinics in Japan. Finally, 20 patients
who met all the inclusion criteria were analyzed. The flow
diagram of patient selection for the analyses is shown in
Figure 1. The clinical characteristics of all 20 patients are
summarized in Table 1. Although the patients’ characteris-
tics were highly variable in their primary origins of cancer,
they all had distant metastases, and 90% of the patients had
already had standard Cx for advanced stage cancer before
the administration of fucoidan.
Changes in Inflammatory Biomarkers
Blood cell counts, including white blood cells, and high-
sensitivity CRP were found to stay stable during the study
(Table 2). However, the 3 main proinflammatory cytokines,
IL-1β, IL-6, and TNF-α, were significantly reduced after 2
weeks of fucoidan administration (Table 2). Other cyto-
kines and all the subsets of lymphocytes except for
CD8+CD28+ T cells were stable without significant change
during the study period (Table 2).
QOL Scores
QOL scores using EORTC QLQ-C30 were all stable except
for an improvement in the financial difficulty score (Table 3).
In contrast to a previous randomized clinical trial, which
showed that fucoidan significantly reduces fatigue caused by
Cx in advanced colorectal cancer patients,29 the average fatigue
score in this study did not improve during the 4-week period.
Prognostic Implication of IL-1β Responsiveness
in Advanced Cancer Patients
To explore the predictive biomarkers in relation to the clini-
cal responsiveness to fucoidan, a subgroup analysis was
conducted between the overall survival (from the start of
fucoidan administration) and the response of inflammatory
biomarkers. Remarkably, univariate analyses with log-rank
tests demonstrated that the patients whose IL-1β level
Table 1. Patient Characteristics.
Total
N= 20 N %
Age (mean, range) 58.9 (18-76)
BMI (mean ± SEM) 21.0 (±0.9)
Sex
Male 12 60.0%
Female 8 40.0%
Primary diagnosis
Lung 4 20.0%
Colon 4 20.0%
Liver 2 10.0%
Pancreas 2 10.0%
Stomach 2 10.0%
Sarcoma 2 10.0%
Uterus 1 5.0%
Breast 1 5.0%
Prostate 1 5.0%
Head and neck 1 5.0%
Histology
Adenocarcinoma 13 65.0%
Squamous cell carcinoma 3 15.0%
Others 4 20.0%
Anticancer therapy before the trial
Surgery 10 50.0%
Chemotherapy 18 90.0%
Radiotherapy 4 20.0%
Baseline laboratory data (mean ± SEM)
WBC (/µL) 6135 (±787)
Hb (g/dL) 11.2 (±0.4)
Plt (×104/µL) 23.1 (±3.0)
Neu (%) 58.2 (±3.2)
Lym (%) 29.5 (±3.2)
High-sensitivity CRP (ng/mL) 20 019 (±7408)
Abbreviations: BMI, body mass index; SEM, standard error of the mean;
WBC, white blood cells; Hb, hemoglobin; Plt, platelet; Neu, neutrophil;
Lym, lymphocyte; CRP, C-reactive protein.
Takahashi et al 5
Table 2. Changes in Inflammatory Biomarkers and QOL Scores.a
N= 20 Day 0 2 Weeks 4 Weeks
P Value (Day 0
to 2 Weeks)
P Value (Day 0
to 4 Weeks)
Baseline laboratory
data (mean ±
SEM)
WBC (/µL) 6135 (±787) 6195 (±704) 1.00
Hb (g/dL) 11.2 (±0.4) 11.4 (±0.4) .98
Plt (×104/µL) 23.1 (±3.0) 24.9 (±3.9) .68
Neu (%) 58.2 (±3.2) 56.1 (±3.2) .79
Lym (%) 29.5 (±3.2) 31.0 (±2.4) .80
N/L 2.7 (±0.4) 2.3 (±0.4) .67
High-sensitivity CRP
(ng/mL)
20 019 (±7408) 21 494 (±8626) 17 738 (±8337) .81 .90
Subsets of
lymphocytes (%)
(mean ± SEM)
T cell (CD3+) 68.8 (±2.9) 64.7 (±3.2) .08
CD4+ T 41.4 (±2.4) 37.6 (±2.4) .10
CD8+ T 23.2 (±1.0) 24.5 (±1.7) .25
CD4 naïve T 32.5 (±3.0) 31.5 (±3.2) .37
CD4 memory T 67.5 (±3.0) 68.5 (±3.2) .37
Treg (CD4+CD25+) 5.6 (±0.7) 7.1 (±1.0) .24
CD8+CD28+ T 58.5 (±4.4) 51.5 (±3.8) .01b
B cell (CD20+) 11.3 (±2.2) 10.9 (±2.6) .47
NK cell 21.2 (±3.0) 25.1 (±2.9) .11
NK subset, CD56+CD16-3.7 (±0.6) 4.2 (±0.8) .31
NK subset, CD56+CD16+15.9 (±2.5) 19.3 (±2.7) .10
NK subset, CD56-CD16+1.5 (±0.5) 1.5 (±0.3) .92
NK (CD56+CD16+)
Perforin+Granzyme B+
89.8 (±3.4) 89.8 (±2.6) .62
NK (CD56+CD16-)
Perforin+Granzyme B+
63.0 (±5.4) 59.0 (±5.1) .28
Cytokines (pg/mL),
(mean ± SEM)
IL-1β358.2 (±62.7) 189.9 (±32.0) 273.4 (±75.2) .01b.16
IL-6 2198.6 (±564.3) 1522.8 (±367.0) 1624.1 (±301.3) .02b.23
TNF-α4819.4 (±772.0) 3257.2 (±648.6) 3985.1 (±548.6) .03b.08
IFN-γ2060.4 (±285.0) 1762.8 (±265.3) 2048.3 (±271.2) .19 .65
IL-2 396.5 (±123.8) 292.3 (±91.2) 421.4 (±136.4) .05 .65
IL-17 81.0 (±16.7) 92.7 (±21.3) 101 (±20.0) .51 .64
IL-23 138.4 (±19.5) 97.8 (±15.7) 100.9 (±18.0) .06 .24
QOL score (mean ± SEM)
Global health status/QoL 58.3 (±5.3) 53.5 (±6.8) 58.3 (±4.8) .25 .92
Functional scales
(higher is better)
Physical functioning 79.7 (±4.5) 76.8 (±5.4) 77.7 (±5.0) .44 .40
Role functioning 76.7 (±6.3) 76.5 (±6.4) 72.5 (±6.5) 1.00 .39
Emotional functioning 82.9 (±3.1) 78.5 (±4.5) 80.8 (±5.0) .63 .91
Cognitive functioning 83.3 (±4.5) 75.4 (±5.9) 80.0 (±5.2) .29 .62
Social functioning 86.7 (±4.3) 76.3 (±6.9) 81.7 (±5.5) .19 .27
Symptom scales
(higher is worse)
Fatigue 35.0 (±4.7) 38.6 (±6.3) 38.6 (±5.5) .93 .40
Nausea and vomiting 6.7 (±2.5) 4.4 (±2.8) 8.3 (±5.3) .50 1.00
Pain 24.2 (±6.1) 20.4 (±6.1) 21.7 (±6.2) .33 1.00
Dyspnea 20.0 (±6.1) 19.3 (±6.4) 18.3 (±6.2) 1.00 1.00
Insomnia 22.8 (±7.7) 19.3 (±5.9) 21.7 (±6.5) 1.00 .78
Appetite loss 25.0 (±6.3) 29.8 (±6.7) 23.3 (±6.0) .53 .77
Constipation 13.3 (±5.6) 12.3 (±5.8) 10.0 (±5.5) 1.00 .63
Diarrhea 23.3 (±7.3) 26.3 (±7.5) 21.7 (±5.0) .80 .81
Financial difficulties 35.0 (±7.0) 31.6 (±8.2) 20.0 (±5.6) .36 <.01b
Abbreviations: QOL, quality of life; SEM, standard error of the mean; WBC, white blood cells; Hb, hemoglobin; Plt, platelet; Neu: neutrophil; Lym,
lymphocyte; CRP, C-reactive protein; CD, cluster of differentiation; NK, natural killer; IL, interleukin; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ.
aBlood samples from 20 patients were collected at day 0, indicating right before fucoidan ingestion, at 2 weeks, indicating ingestion of fucoidan for 2
weeks, and at 4 weeks, indicating ingestion of fucoidan for 4 weeks, and used for biochemical analyses. QOL scores were calculated using the European
Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) submitted by the participants.
bP < .05.
6 Integrative Cancer Therapies
decreased during the first 2 weeks (IL-1β responders) had a
significantly longer survival rate compared with the prog-
noses for IL-1β nonresponders (median survival time =
13.0 vs 5.0 months, respectively; P = .02, Figure 2).
Compared with IL-1β, the responsiveness of the other
inflammatory biomarkers, including high-sensitivity CRP,
IL-6, and TNF-α, were not correlated with survival.
Multivariate analysis using a Cox proportional hazards
regression model also revealed that the responsiveness of
IL-1β was the only significant independent prognostic fac-
tor in all the 20 patients (hazard ratio = 0.08, 95% CI =
0.007-0.588, P = .01; Table 3, Figure 2).
Discussion
The present exploratory clinical study revealed that the lev-
els of the major proinflammatory cytokines, including
IL-1β, significantly decreased during the first 2 weeks after
the administration of fucoidan in the advanced cancer
patients. Although we have to be cautious about overesti-
mating these results because of the lack of a control group
and a small number of patients, this exploratory clinical
study revealed that there are some responders who can ben-
efit from using fucoidan by achieving an anti-inflammatory
effect in a short time.
Targeting inflammation in cancer patients is a promising
approach not only for alleviating cancer-related symptoms
as supportive care but also for enhancing clinical effi-
cacy.2-7,11 Inflammatory responses are mediated by multiple
factors, such as proinflammatory cytokines IL-1β, IL-6, and
TNF-α.1-7 These cytokines play a pivotal role in establishing
a suitable microenvironment for tumor development and
metastasis4,5 and also in diminishing therapeutic efficacy.7
Among proinflammatory cytokines, IL-1β is thought to be a
key factor in the initiation of inflammatory cascades.36,37 It
activates multiple intracellular pathways to initiate the pro-
duction of factors such as IL-6, IL-8, matrix metalloprotein-
ases, and vascular endothelial growth factor, which promote
tumor growth and metastasis.11,38-40 Clinically, it has been
shown that elevated serum concentrations of IL-1β were
detected in patients with infectious or inflammatory condi-
tions, including cancer.8-10 In particular, the survival time
was reported to be shorter in advanced cancer patients with
high proinflammatory cytokine levels.11-13 Furthermore,
IL-1β was more closely associated with symptoms of cancer
cachexia such as loss of appetite, weight loss, and sarcope-
nia when compared with IL-6 or TNF-α.12 Therefore, the
therapeutic approach of IL-1β blockade in cancer patients is
expected to be an effective intervention in various cancer
progression stages.11,37 Moreover, fucoidan inhibits the via-
bility and invasiveness, and induces apoptosis in IL-1β
treated human rheumatoid arthritis fibroblast synoviocytes.41
Combining these studies with our present results, fucoidan
could well be one of the therapeutic options targeting inflam-
mation in advanced cancer patients. Recently, the effect of a
combined use of low-molecular-weight fucoidan fractions
(mainly 760 Da) with gemcitabine and cisplatin, 2 sub-
stances that are standard Cx agents for advanced bladder
cancer, was studied, and it was observed that fucoidan could
ameliorate cachexia-associated muscle atrophy in bladder
Table 3. Univariate and Multivariate Analyses Between the Inflammatory Responsiveness and Overall Survival From the Beginning of
Fucoidan Ingestion.a
Inflammatory Responsiveness
N = 20
MST
Log-Rank Test Cox’s Hazard Regression
Cases P Value Hazard Ratio 95% CI P Value
High-sensitivity CRP
Responder (day 0 > 2w) 10 8 .54 1.22 0.216-7.078 .82
Nonresponder (day 0 2w) 10 11 0.82
IL-1β
Responder (day 0 > 2w) 15 13 .02b0.08 0.007-0.588 .01b
Nonresponder (day 0 2w) 5 5 12.87
IL-6
Responder (day 0 > 2w) 13 13 .28 0.55 0.108-2.452 .43
Nonresponder (day 0 2w) 7 8 1.83
TNF-α
Responder (day 0 > 2w) 14 8 .13 5.87 0.970-59.162 .05
Nonresponder (day 0 2w) 6 13 0.17
Abbreviations: MST, median survival time; 2w, 2 weeks; CRP, C-reactive protein; IL, interleukin; TNF-α, tumor necrosis factor-α.
aPatients (n = 20) were grouped according to the responsiveness to each inflammatory factor (far left column) after comparing day 0 with 2w, and
survival curve comparisons of each factor were conducted with the log-rank test. Multivariate analysis using a Cox proportional hazards regression
model was performed to confirm the role of these inflammatory factors related to the overall survival from the beginning of fucoidan ingestion. The
univariate and multivariate analyses revealed that the responsiveness of IL-1β was a significant independent prognostic factor (P < .05).
bP < .05.
Takahashi et al 7
cancer–bearing mice. Additionally, these researchers found
that inflammatory cytokines such as TNF-α, IL-6, and IL-1β
were suppressed by fucoidan, which is in line with our
results.42
Fatigue in advanced cancer patients is associated with pro-
inflammatory cytokines such as IL-1β, IL-6, and TNF-α.43 In
contrast to our expectation and although a previous ran-
domized clinical trial showed that fucoidan alleviated
Cx-induced fatigue,31 in the present study, QOL scores,
including fatigue, were almost stable and did not show an
important improvement in spite of the significant cytokine
reduction. Such discrepant results are likely a result of the
individual patient status in fatigue development and the type
of questionnaire used. In this exploratory study, the EORTC
QLQ-C30 questionnaire was chosen to evaluate the general
and comprehensive grades of various aspects of patients’
QOL because the recruited patients represented the diverse
symptomatic conditions associated with advanced cancer
progression stages. On the other hand, in a previous trial,31
the National Cancer Institute Common Toxicity Criteria
assessed the grades of the specific toxicity caused by Cx for
advanced colorectal cancer patients. Additionally, Cx is
known to induce inflammatory reactions via proinflamma-
tory cytokines, which are associated with Cx-related side
effects, including fatigue.43-46 In future studies, it may be
needed to focus specifically on Cx-related fatigue and also
choose an appropriate questionnaire to detect the change in
Cx-related side effects.
It is noteworthy that univariate and multivariate analyses
of the data obtained in this study showed a correlation
between prognosis and IL-1β responsiveness. However,
because of the design of this study, which included a hetero-
geneous population of patients without a control group, it is
difficult to draw any definitive conclusions because various
biases cannot be excluded. Nevertheless, there was no sig-
nificant difference in the characteristic baseline variables of
the patients between the group of IL-1β responders and
those of nonresponders, except for sex distribution (Online
Supplement 1). Interestingly, the levels of the other major
proinflammatory cytokines, TNF-α and IL-6, also signifi-
cantly decreased in the group of IL-1β responders (P < .05)
but not in the group of IL-1β nonresponders (Online
Supplement 2). High serum concentrations of these proin-
flammatory cytokines are usually associated with a reduced
survival rate.11,13 In addition, cancer patients often exhibit
higher IL-1β plasma levels, suggesting a systemic role of
this factor.39 It has also been shown that tumor cells secrete
IL-1β, triggering an indirect upregulation of IL-6 and other
multiple factors, thereby promoting tumor growth and
metastasis.4,39 Taken together with these facts, the results
obtained in this study seem feasible and may lead us to
believe that the responsiveness of IL-1β in the first 2 weeks
might predict a prolonged survival as a result of fucoidan
administration. It is also interesting that the QOL score
relating to the financial difficulty was significantly
improved only in the group of IL-1β responders (Online
Figure 2. Comparison of the overall survival from the beginning of fucoidan administration, between IL-1β responders and
nonresponders. Overall survival from the beginning of fucoidan administration was monitored. Responders were patients whose IL-1β
level decreased during the first 2 weeks. Nonresponders were patients whose IL-1β level did not decrease during the first 2 weeks.
Abbreviation: IL, interleukin; MST, median survival time.
8 Integrative Cancer Therapies
Supplement 2). Accordingly, the previous randomized clini-
cal trial already reported a similar favorable prognosis in
the fucoidan group with Cx.31 Because inflammatory reac-
tions induced by Cx usually result in many side effects and
also affect therapeutic efficacy,7 fucoidan could be used to
target proinflammatory cytokine effects as supportive care
for cancer patients especially undergoing Cx.11,22,47
However, further prospective, larger randomized clinical
studies will be needed to clarify whether the responsiveness
of IL-1β is a reliable predictive biomarker for patients with
advanced cancer receiving fucoidan.
Finally, we must also address the fact that IL-1β, IL-6, and
TNF-α levels decreased after 2 weeks of fucoidan adminis-
tration but returned to pretreatment levels after 4 weeks.
Perhaps the fucoidan dose was not enough, or the period of
treatment was too short, or the monitoring time point at 4
weeks may just be a transition phase from cytokine markers
to other markers (eg, lymphocyte subsets; Table 2). Still
another likely alternative to explain this cytokine fluctuation
is the speculation that fucoidan’s effect on some cell surface
receptors is weakened at around 4 weeks post–fucoidan
ingestion because fucoidan has been postulated to downregu-
late some transcription factors involved in survival, prolifera-
tion, apoptosis, invasion, metastasis, and angiogenesis via
receptors (eg, EGF receptor and receptor tyrosine kinase).21
However, the reasons for this instability remain to be solved.
Conclusions
This exploratory prospective clinical study for advanced can-
cer patients revealed that levels of important proinflamma-
tory cytokines, including IL-1β, IL-6, and TNF-α, were
significantly reduced after a short period of fucoidan admin-
istration. Interestingly, a subgroup analysis showed that the
responsiveness of IL-1β was significantly correlated with the
overall survival and suggested that this responsiveness might
be a useful prognostic biomarker for advanced cancer patients
receiving fucoidan. To the best of our knowledge, this is the
first study to provide evidence of the anti-inflammatory
effects of fucoidan for advanced cancer patients. In the future,
larger controlled trials are required to establish the efficacy of
fucoidan, especially for advanced cancer patients undergoing
Cx as supportive care.
Authors’ Note
Trial Registration Number: UMIN000024066; retrospectively
registered on September 15, 2016 (UMIN-CTR: http://www.umin.
ac.jp/ctr/index.htm). The data sets generated and analyzed during
the current study are available from the corresponding author on
reasonable request.
Acknowledgments
The authors express appreciation to the participants, investigators,
and all other individuals involved in the present study.
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) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: The
study was funded by Daiichi Sangyo Co, Ltd, Osaka, Japan. The
funder provided support in the form of research materials but did
not have any additional role in the study design, data collection
and analysis, decision to publish, or preparation of the article.
Supplemental Material
The Online Supplementary files are available at http://journals.
sagepub.com/doi/suppl/10.1177/1534735417692097
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    ... This may have affected the statistical analysis; therefore, further studies are needed to confirm the potential effects of fucoidan on NK cell activity using a large number of subjects. The proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) were reported to be reduced after fucoidan ingestion (13). Since cancer and inflammatory responses are closely associated, we need to assess the relationship between inflammatory markers and levels of fucoidan and NK cells/immunoglobulins. ...
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  • ... Fucoidans also interfere which cell invasion and attachment to fibronectin by competing mechanisms; affect the inflammatory response [112,113] and may also help to the immune system, increasing the number and activity of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells [50,114,115], also reducing the toxicity of chemotherapies [115]. Taking all available data together, fucoidans are strong candidates to be used as adjuvants in cancer therapies [21,99,114,116]. ...
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  • ... The results of the experiment showed that major proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α), showed a significant decrease after 2 weeks of continuous ingestion of fucoidan. But the quality of life scores, including fatigue, did not change significantly during the study period [79]. Shreya et al. investigeted the effects of fucoidan extracted from Undaria pinnatifida on the pharmacokinetics of two common used hormone therapies, letrozole and tamoxifen, in breast cancer patients. ...
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  • ... Additional studies have demonstrated fucoidans utility in reducing inflammation in cancer patients [34]. No interactions or adverse effects were observed with the commonly used hormone therapies tamoxifen and letrozole in breast cancer patients. ...
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    Glucocorticoids are among the most effective anti-inflammatory drugs, and are widely used for cancer therapy. Unfortunately, chronic treatment with glucocorticoids results in multiple side effects. Thus, there was an intensive search for selective glucocorticoid receptor (GR) activators (SEGRA), which retain therapeutic potential of glucocorticoids, but with fewer adverse effects. GR regulates gene expression by transactivation (TA), by binding as homodimer to gene promoters, or transrepression (TR), via diverse mechanisms including negative interaction between monomeric GR and other transcription factors. It is well accepted that metabolic and atrophogenic effects of glucocorticoids are mediated by GR TA. Here we summarized the results of extensive international collaboration that led to discovery and characterization of Compound A (CpdA), a unique SEGRA with a proven " dissociating " GR ligand profile, preventing GR dimerization and shifting GR activity towards TR both in vitro and in vivo. We outlined here the unusual story of compound's discovery, and presented a comprehensive overview of CpdA ligand properties, its anti-inflammatory effects in numerous animal models of inflammation and autoimmune diseases, as well as its anti-cancer effects. Finally, we presented mechanistic analysis of CpdA and glucocorticoid effects in skin, muscle, bone, and regulation of glucose and fat metabolism to explain decreased CpdA side effects compared to glucocorticoids. Overall, the results obtained by our and other laboratories underline translational potential of CpdA and its derivatives for treatment of inflammation, autoimmune diseases and cancer.
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    There is an actual tendency towards bioactive natural products with applications in various industries, such as pharmaceutical, biomedical, cosmetics and food. This has put some emphasis in research on marine organisms, including macroalgae and microalgae, among others. Polysaccharides with marine origin constitute one type of these biochemical compounds that already proved to have several important properties, such as anticoagulant and/or antithrombotic, immunomodulatory ability, antitumor and cancer preventive, antilipidaemic and hypoglycaemic, antibiotics and anti-inflammatory and antioxidant, making them promising bioactive products and biomaterials with a wide range of applications. Their properties are mainly due to their structure and physicochemical characteristics, which depend on the organism they are produced by. In the biomedical field, the polysaccharides from algae can be used in controlled drug delivery, wound management, and regenerative medicine. This review will focus on the biomedical applications of marine polysaccharides from algae.
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    Fucoidan, a sulfated polysaccharide purified from brown algae, has a variety of immune-modulation effects, such as promoting activation of dendritic cells (DCs), natural killer (NK) cells and T cells, and enhancing anti-viral and anti-tumor responses. However, the immune-modulatory effect of fucoidan from different seaweed extracts has not been thoroughly analyzed and compared. We analyzed fucoidans obtained from Ascophyllum nodosum (A. nodosum), Macrocystis pyrifera (M. pyrifera), Undaria pinnatifida (U. pinnatifida) and Fucus vesiculosus (F. vesiculosus) for their effect on the apoptosis of human neutrophils, activation of mouse NK cells, maturation of spleen DCs, proliferation and activation of T cells, and the adjuvant effect in vivo. Fucoidans from M. pyrifera and U. pinnatifida strongly delayed human neutrophil apoptosis at low concentration, whereas fucoidans from A. nodosum and F. vesiculosus delayed human neutrophil apoptosis at higher concentration. Moreover, fucoidan from M. pyrifera promoted NK cell activation and cytotoxic activity against YAC-1 cells. In addition, M. pyrifera fucoidan induced the strongest activation of spleen DCs and T cells and ovalbumin (OVA) specific immune responses compared to other fucoidans. These data suggest that fucoidan from M. pyrifera can be potentially useful as a therapeutic agent for infectious diseases, cancer and an effective adjuvant for vaccine.