Journal of the American Nutrition Association

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A Botanical Drug Extracted From Antrodia

cinnamomea: A First-in-human Phase I Study in
Healthy Volunteers

Yu-Tso Liao, Kai-Wen Huang, Wan-Jing Chen & Tzung-Hsien Lai

To cite this article: Yu-Tso Liao, Kai-Wen Huang, Wan-Jing Chen & Tzung-Hsien Lai (2023)
A Botanical Drug Extracted From Antrodia cinnamomea: A First-in-human Phase I Study
in Healthy Volunteers, Journal of the American Nutrition Association, 42:3, 274-284, DOI:
10.1080/07315724.2022.2032868

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Journal of the American College of Nutrition
2023, VOL. 42, NO. 3, 274–284
https://doi.org/10.1080/07315724.2022.2032868

A Botanical Drug Extracted From Antrodia cinnamomea: A First-in-human

Phase I Study in Healthy Volunteers
Yu-Tso Liaoa,b, Kai-Wen Huanga,c,d, Wan-Jing Chene and Tzung-Hsien Laie
a
Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei City, Taiwan; bDivision of Colorectal Surgery,
Department of Surgery, Biomedical Park Hospital, National Taiwan University Hospital, Taipei City, Taiwan; cDepartment of Surgery, National
Taiwan University Hospital, Taipei City, Taiwan; dHepatitis Research Center, National Taiwan University Hospital, Taipei City, Taiwan; eTaiwan
Leader Biotech Corp, Taipei City, Taiwan

ABSTRACT ARTICLE HISTORY

Objective: LEAC-102 is an emerging drug extracted from the medicinal fungus Antrodia cinnamomea Received 27 September 2021
(AC), which is traditionally used to ameliorate fatigue and liver disorders arising from excessive Accepted 18 January 2022
alcohol consumption. AC has been used as a health product with an immunomodulatory function, KEYWORDS
but its anticancer effect has not been applied in clinical therapy as a drug. This first-in-human Antrodia cinnamomea; clinical
study examined the safety and tolerability of LEAC-102 as a new drug in healthy adults. trials; first-in-human; herbal
Method: This standard 3 + 3 dose-escalation study included 18 participants administered LEAC-102 medicine; immunomodulation;
at doses of 597.6, 1195.2, 1792.8, 2390.4, or 2988 mg/day for 1 month plus 7 days of safety follow-up. safety
The maximum planned dose was 2988 mg. Dose-limiting toxicity (DLT) was monitored from the
start of LEAC-102 administration up to the final visit. The dose of LEAC-102 was escalated to the
subsequent cohort as long as there was no DLT in the previous cohort. Tolerability, clinical status,
safety (by laboratory parameters), and adverse event occurrence were documented weekly during
the treatment and 1 week after the conclusion of the treatment.
Results: All clinical biochemistry profiles were in the normal range, and no serious adverse effects
were observed. The maximum tolerated dose of LEAC-102 was determined to be 2988 mg/day
because one participant experienced urticaria. Additionally, our exploratory objectives revealed that
LEAC-102 significantly elevated natural killer, natural killer T, and dendritic cells in a dose-dependent
manner, activated effector T cells, and upregulated programmed cell death-1 expression.
Conclusions: The outcomes suggested that LEAC-102 was well tolerated and safe in healthy adults
and exhibited potential immunomodulatory function.

ABBREVIATIONS: AC: Antrodia cinnamomea; ACTH: adrenocorticotropin; AE: adverse event; BMI:
body mass index; DC: dendritic cell; DLT: dose-limiting toxicity; E2: estradiol; ECG: electrocardiogram;
EOT: end of treatment; HPLC: high-performance liquid chromatography; MTD: maximum tolerated
dose; NF-κB: nuclear factor kappa B; NK: natural killer; PBMC: peripheral blood mononuclear cells;
PD-1: programmed cell death-1

Introduction lignans, benzenoids, and glycoproteins (2). AC is tradition-

ally used by indigenous people to ameliorate fatigue and
Herbal medicines extracted from natural products have a liver disorders arising from excessive alcohol consumption
uniquely diverse composition and comprise a variety of (3). Gradually, the use of AC as a health food has increased
multidimensional chemical structures, leading to the mul- due to its numerous biological activities including
tiplicity of their biological activities and druglike properties. liver-protective, anti-inflammatory, antioxidant, antihyper-
Some natural products have been developed into emerging tensive (4), cholesterol-lowering (5), anticancer (6), and
drugs for the treatment of human diseases and have had a immunomodulatory effects (7).
profound impact on biomedicine (1). The traditional use of AC indicates its protective effects
Antrodia cinnamomea (AC), a medical mushroom, is a in the liver. Many studies have shown that AC activates
unique edible fungus that grows on Cinnamomum kanehirai nuclear factor erythroid 2–related factor 2 and increases the
in Taiwan and comprises a complex mixture of biological expression of antioxidant genes to promote liver function
compounds, including terpenoids, polysaccharides, maleic and protect against hepatotoxicity in rats (8, 9). AC also
and succinic acid derivatives, benzoquinone derivatives, reverses carbon tetrachloride–induced liver fibrosis in rats

CONTACT Kai-Wen Huang [email protected] Department of Surgery & Hepatitis Research Center, National Taiwan University Hospital, No. 7
Chung-Shan South Rd, Taipei 10002, Taiwan
Supplemental data for this article is available online at https://doi.org/10.1080/07315724.2022.2032868.
© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
 Journal of the American College of Nutrition 275

by reducing serum glutamic oxaloacetic transaminase and with the relevant guidelines and regulations. All study par-
serum glutamate pyruvate transaminase levels (10). ticipants provided informed consent prior to participation
Furthermore, AC also exhibits suppressive effects on tum- in the investigation, and the study was supported by Taiwan
origenesis. AC extracts inhibited hepatocellular carcinoma Leader Biotech Corp. Ltd.
cell survival by upregulating the expression of an inhibitor
of nuclear factor kappa B (NF-κB) in the cytoplasm and
decreasing the activity of NF-κB in the nucleus (11). Further Participants
cancer-related AC research has emerged in recent years in Eighteen healthy participants aged 20 to 44 years with a
addition to the studies of its role in hepatocellular carci- body mass index (BMI) of 18.5 to 24.0 kg/m2 and clinically
noma. Several in vitro and in vivo studies have revealed normal hematology, biochemistry, and urinalysis determi-
that AC attenuates tumor invasion and migration by inhib- nations were included. All participants confirmed to be
iting the self-renewal and proliferation capacities of cancer healthy by the investigator based on medical history, clinical
stem cells in head and neck squamous cell carcinoma and examination, chest x-rays, and electrocardiogram (ECG)
lung, breast, and colorectal cancer (2, 12, 13). were eligible. Participants with a previous or current history
Recently, the immunomodulatory effect of AC was found of clinically significant allergy, hypersensitivity associated
to be related to the inhibition of tumor progression. The with AC, cardiac failure, autoimmune diseases, psychiatric
purified polysaccharide component of AC indirectly blocks disorders, HIV infection, or hepatitis B or C were excluded.
tumor progression by enhancing immunomodulatory capac- Those using AC products within 1 month prior to the
ities, promoting a Th1-dominant state and natural killer screening visit were also excluded from this trial. Female
(NK) cell activity in an animal model (14). A ubiquinone volunteers were not pregnant, lactating, or taking contra-
derivative isolated from AC was suggested to promote the ceptives at the time of recruitment.
antitumor immune response of immature dendritic cells
toward liver cancer stem cells (15). A case report also
revealed that AC improved quality of life and immune func- Study design
tion and reduced the occurrence of adverse effects associated
with chemotherapy in patients with small cell lung can- The volunteers were divided into 5 cohorts (dose levels A,
cer (16). B, C, D, E) with up to 6 evaluable healthy volunteers per
Although AC has been demonstrated to be beneficial in cohort for the assessment of the MTD. The A through E
cancer treatment as a synergistic therapy and promoter of dose levels of LEAC-102 were 597.6, 1195.2, 1792.8, 2390.4,
immune system efficacy, the clinical safety data of AC are and 2988 mg/day, respectively. Volunteers who were admin-
still insufficient. In particular, one challenge regarding the istered LEAC-102 were sequentially enrolled to receive 1,
use of AC is that the tolerable dose in humans and the 2, 3, 4, or 5 LEAC-102 capsules (199.2 mg/capsule) alone
clinical effects remain unclear and controversial. Therefore, before a meal 3 times a day. At least 1 day elapsed between
we conducted a phase I study to evaluate the physiological the beginning of LEAC-102 administration in the first 3
profiles of LEAC-102, a novel botanical drug extracted from healthy volunteers of each cohort.
AC, as a single agent in healthy human participants to We arranged visits on days 1, 8, 15, and 22, which were
determine the recommended dose for patients with cancer scheduled as visits 1, 2, 3, and 4 for safety observation, and
in the future. The primary objective of this trial was to volunteers were required to remain on-site for at least 1 hour
determine the maximum tolerated dose (MTD) of LEAC-102 after taking LEAC-102. Visit 5 was scheduled on day 29 for
as a single agent based on the dose-limiting toxicity (DLT) checking status of the end of treatment (EOT) and con-
observed in healthy volunteers. The secondary study objec- ducted exploratory items.
tives were to evaluate the safety and tolerability profiles of The starting dose of LEAC-102 was determined based
LEAC-102 alone in healthy volunteers and to perform on the results of preclinical toxicity studies (17) and no
immune assessment as the exploratory objective. observed adverse effect level of LEAC-102 was determined
as 1700 mg/kg/day in rats of both sexes, leading to human
equivalent dose of 274.2 mg/kg/day. Based on these data, a
starting dose of LEAC-102 with 597.6 mg/day was considered
Material and methods
to be a safe starting dosage for humans.
Study overview DLT was defined as any ≥ grade 2 adverse event (AE)
causally related to LEAC-102 administration as judged by
This was an open-label, single-arm dose-escalation study of the investigator according to the National Cancer Institute
LEAC-102 to evaluate its safety and tolerability. To deter- Common Terminology Criteria for Adverse Events (NCI
mine the MTD of LEAC-102, a single arm with traditional CTCAE) version 5.0. DLT was monitored from the start of
3 + 3 dose-escalation (involving a total of 5 dose levels) was LEAC-102 administration up to visit 6 (final visit after 28
applied in this trial. This prospective study was approved consecutive days of treatment plus 7 days of safety follow-up).
by the ethics committee (ethical approval number: The dose of LEAC-102 was escalated to the subsequent
201802057MSC) and the Institutional Review Board of the cohort as long as there was no DLT in the previous cohort.
National Taiwan University Hospital (Protocol ID: LEAC-102- The MTD was defined as the highest dose level at which
01), and all study methods were performed in accordance <2 of 6 healthy volunteers experienced DLT. Each cohort
276 Y.-T. LIAO ET AL.

included up to 6 volunteers according to the 3 + 3 design. CD25-AlexaFluor®488, CTLA-4-PE, CD33-FITC, CD39-PE,

The MTD should be tested in 6 healthy volunteers. No CD11c-APC, PD-1-AlexaFluor®488, PD-L1-PE, CD14-PE
volunteer could be assigned to more than one dose level. Cy5.5, and CD11c-APC. Data acquisition was performed
All dose escalation/de-escalation decisions were made by using a Navios flow cytometer (Beckman Coulter) and ana-
the safety monitoring committee. lyzed by Kaluza software version 2.1 (Beckman Coulter).

Drug product Statistical analyses

LEAC-102 was isolated from AC mycelia and fruit bodies Baseline characteristics are presented using descriptive sta-
using the extraction technology of the Taiwan Leader Biotech tistics and displayed by dose level. Additionally, descriptive
Corp. We analyzed the powdered LEAC-102 material by statistics are provided for all of the end points by dose level.
high-performance liquid chromatography (HPLC) to identify Descriptive statistics, including the number of observations,
the major compounds (Supplementary material, Figure S1). mean, and standard deviation (SD), are presented for the
raw data as well as changes from the baseline. The count
and percentages were used to summarize the categorical
Measurements data. Statistical analysis was performed using SAS for
For safety assessments, the incidence of AEs/serious adverse Windows software (Version 9.4, SAS Inc., USA). Paired
events and vital signs were recorded and physical examina- Student’s t test was applied to analyze the raw numerical
tion assessments, biochemistry analyses, hematology analy- results. Unpaired Student’s t test was applied to analyze the
ses, urinalysis tests, and 12-lead ECGs were performed for percentage changes in the immune analysis.
this study. The determination of the MTD was based on AEs observed during the study were coded using the
the occurrence of DLT. up-to-date version of the Medical Dictionary for Regulatory
The changes in lymphocyte activities, innate immune Activities (MedDRA) and were reported by dose level by
cells, adaptive immune cells, bridge cells, regulatory cells, system organ class and the preferred term classified in the
and cytokine levels were assessed as exploratory end points. MedDRA as appropriate. The toxicity grades of the AEs
In addition, the changes in serum levels of adrenocorti- were rated according to the NCI CTCAE version 5.0. Net
cotropin (ACTH), cortisol, progesterone, testosterone, and changes from pretreatment laboratory test results and vital
estradiol (E2) as well as the volume of the adrenal gland signs were analyzed by descriptive statistics.
as measured by ultrasound were evaluated as exploratory
safety end points in this study. Results
Baseline characteristics
Materials and reagents
A standard 3 + 3 dose-escalation study was employed to eval-
Reagents and materials used in this research included uate the safety and tolerability of LEAC-102. A total of 18
Ficoll-Paque PREMIUM (GE Healthcare, Massachusetts, USA), healthy participants were recruited to receive the indicated
staining buffer (homemade reagent), Pasteur pipettes, 1.5-mL dose of LEAC-102 (597.6, 1195.2, 1792.8, 2390.4, or 2988 mg/
Eppendorf tubes (Volac, Royston, UK), 15 mL and 50-mL plastic day). We also identified major compounds of LEAC-102 pow-
centrifuge and FACS™ tubes (Thermo Fisher Scientific, Corning, der by HPLC, including 25S-Antcin H, 25 R-Antcin H,
USA), Thermo Scientific Nunc serological pipettes (Thermo 25S-Antcin B, 25S-Antcin K, and 25 R-Antcin B (Figure 1).
Fisher Scientific, Corning, USA), and 96-well plates (V bottom The groups that received dose levels A to D (n = 3) and dose
for cell counting) (Merck, Darmstadt, Germany). level E (n = 6) were Intention-to-treat (ITT)- and MTD-evaluable
populations. Only one participant who received dose level E
did not complete the entire trial due to DLT (Table 1). The
Isolation of peripheral blood mononuclear cells
age, body weight, and BMI of the participants were similar
(PBMCs)
among the LEAC-102 dose levels (Table 2).
Human PBMCs were isolated from buffy coats by the Ficoll
density gradient centrifugation technique (Ficoll-Paque™
PREMIUM; GE Healthcare, USA). After centrifugation, Safety
PBMCs were washed with 1X PBS and resuspended in stain- There were no significant changes in body weight, diastolic
ing buffer (2% FBS + 0.02% NaN3 in 1× PBS) for cell blood pressure, or pulse rate in any participant after
surface marker staining or intracellular staining. LEAC-102 administration. Although systolic blood pressure
was elevated at dose levels A and C (108.0 and 120.0 mm
Hg) compared with baseline, no clinically relevant effects
Staining and flow cytometry
were noted (Table 3). The mean total bilirubin of all par-
PBMCs were prepared from the peripheral blood and stained ticipants was significantly decreased at the end point, but
for cell surface markers, including TCR-FITC, CD25-PE, the value was within the clinically normal range (Table 4).
CD45-ECD, PD-1-PE Cy5, CD4-PE Cy7, TCR-APC, Biochemistry parameters, including renal function
 Journal of the American College of Nutrition 277

Figure 1. Major compounds of LEAC-102 powder. (A) 25R/S-Antcin B, (B) 25R/S-Antcin K, and (C) 25R/S-Antcin H were primary compounds of LEAC-102 powder
and analyzed by high-performance liquid chromatography (HPLC).

Table 1. Summary of Participant Disposition.

All participants Dose level A Dose level B Dose level C Dose level D Dose level E
Variable (N = 18) (n = 3) (n = 3) (n = 3) (n = 3) (n = 6)
Eligible, n (%) 18 (100.0%) 3 (100.0%) 3 (100.0%) 3 (100.0%) 3 (100.0%) 6 (100.0%)
Complete the study, n (%) 17 (94.4%) 3 (100.0%) 3 (100.0%) 3 (100.0%) 3 (100.0%) 5 (83.3%)
Volunteer experiences DLT, n (%) 1 (5.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (16.7%)
ITT population, n (%) 18 (100.0%) 3 (100.0%) 3 (100.0%) 3 (100.0%) 3 (100.0%) 6 (100.0%)
MTD evaluable population, n (%) 18 (100.0%) 3 (100.0%) 3 (100.0%) 3 (100.0%) 3 (100.0%) 6 (100.0%)
Abbreviations: MTD = maximum tolerated dose; DLT = dose-limiting toxicity; ITT = intent-to-treat.

Table 2. Demographic Characteristics of Participants.

All participants Dose level A Dose level B Dose level C Dose level D Dose level E
Variable (N = 18) (n = 3) (n = 3) (n = 3) (n = 3) (n = 6)
Age, y 32.3 ± 5.18 37.7 ± 1.53 27.7 ± 4.51 29.7 ± 5.51 35.0 ± 6.08 31.8 ± 4.02
Male, n (%) 10 (55.6%) 1 (33.3%) 3 (100.0%) 1 (33.3%) 1 (33.3%) 4 (66.7%)
Body weight (kg) 63.6 ± 8.13 61.7 ± 8.58 67.1 ± 4.93 66.9 ± 2.40 62.3 ± 12.57 61.7 ± 9.96
BMI (kg/m )
2
21.9 ± 1.40 22.3 ± 0.42 21.9 ± 0.23 22.9 ± 1.25 21.8 ± 1.02 21.4 ± 2.10
Abbreviation: BMI = body mass index.
Data are presented as mean ± standard deviation or n (%).

Table 3. Body Weight and Blood Pressure Profiles in Participants

All participants Dose level A Dose level B Dose level C Dose level D Dose level E
Variable (N = 18) (n = 3) (n = 3) (n = 3) (n = 3) (n = 6)
Body weight (kg)
Baseline 63.6 ± 8.13 61.7 ± 8.60 67.1 ± 4.50 66.9 ± 2.40 62.3 ± 12.60 61.8 ± 9.96
 EOT/ET 63.8 ± 7.73 61.7 ± 8.41 67.0 ± 4.30 67.4 ± 2.81 62.5 ± 12.24 62.1 ± 9.13
Systolic BP (mm Hg)
Baseline 114.6 ± 13.23 102.3 ± 10.97 118.3 ± 11.50 115.7 ± 5.13 115.3 ± 12.86 117.8 ± 17.47
 EOT/ET 114.7 ± 14.69 108.0 ± 10.39* 123.0 ± 18.52 120.3 ± 5.03* 110.0 ± 20.81 113.3 ± 16.34
Diastolic BP (mm Hg)
Baseline 69.0 ± 9.13 65.0 ± 3.61 71.0 ± 6.93 67.3 ± 10.79 64.0 ± 4.00 73.3 ± 12.44
 EOT/ET 68.3 ± 6.84 63.0 ± 1.00 72.7 ± 9.29 70.7 ± 4.51 64.3 ± 6.81 69.5 ± 7.40
Pulse rate (beats/min)
Baseline 76.6 ± 8.96 63.3 ± 6.66 82.7 ± 5.03 74.7 ± 5.03 74.7 ± 5.13 82.0 ± 7.56
 EOT/ET 77.5 ± 7.26 72.7 ± 7.57 80.0 ± 2.00 71.7 ± 5.03 79.0 ± 9.85 80.8 ± 7.28
Abbreviations: BP = blood pressure; EOT = end of treatment; ET = early termination.
Data are presented as mean ± standard deviation.
*Dose level was significantly different with baseline, p < 0.05.
278 Y.-T. LIAO ET AL.

Table 4. Plasma Liver Function Profiles in Participants

All participants Dose level A Dose level B Dose level C Dose level D Dose level E
Variable (N = 18) (n = 3) (n = 3) (n = 3) (n = 3) (n = 6)
Total protein (g/dL)
Baseline 7.4 ± 0.36 7.4 ± 0.00 7.4 ± 0.42 7.5 ± 0.25 7.2 ± 0.21 7.5 ± 0.55
 EOT/ET 7.4 ± 0.41 7.3 ± 0.25 7.6 ± 0.23 7.2 ± 0.53 7.2 ± 0.35 7.6 ± 0.50
Alkaline phosphatase (U/L)
Baseline 50.2 ± 13.17 44.0 ± 10.82 58.7 ± 22.14 51.7 ± 19.50 42.7 ± 7.23 52.0 ± 8.27
 EOT/ET 49.9 ± 13.33 45.7 ± 9.29 54.7 ± 19.50 44.0 ± 20.30 43.0 ± 11.27 56.2 ± 8.98
Alanine aminotransferase (U/L)
Baseline 16.8 ± 7.53 13.7 ± 7.02 18.3 ± 5.86 20.0 ± 11.27 15.0 ± 10.44 16.8 ± 7.05
 EOT/ET 15.6 ± 6.78 13.0 ± 6.08 17.7 ± 4.73 13.3 ± 3.79 10.7 ± 3.79 19.3 ± 8.96
Albumin (g/dL)
Baseline 4.6 ± 0.23 4.5 ± 0.30 4.7 ± 0.15 4.8 ± 0.21 4.5 ± 0.06 4.5 ± 0.27
 EOT/ET 4.6 ± 0.31 4.6 ± 0.45 4.8 ± 0.36 4.6 ± 0.27 4.5 ± 0.17 4.5 ± 0.35
Gamma-GT (U/L)
Baseline 16.4 ± 8.64 23.3 ± 19.63 14.0 ± 2.65 19.7 ± 6.66 11.7 ± 1.53 15.0 ± 4.90
 EOT/ET 15.5 ± 8.62 22.3 ± 17.90 13.0 ± 2.65 15.3 ± 6.66 10.3 ± 0.58 16.0 ± 7.46
Total bilirubin (mg/dL)
Baseline 0.85 ± 0.254 1.15 ± 0.121 0.83 ± 0.280 0.78 ± 0.107 0.92 ± 0.219 0.71 ± 0.275
 EOT/ET 0.67 ± 0.348* 0.68 ± 0.265 1.01 ± 0.619 0.51 ± 0.067 0.61 ± 0.203 0.59 ± 0.339
Abbreviations: EOT = end of treatment; ET = early termination.
Data are presented as mean ± standard deviation.
*Dose level was significantly different with baseline, p < 0.05.

Table 5. Plasma Renal Function Profiles in Participants

All participants Dose level A Dose level B Dose level C Dose level D Dose level E
Variable (N = 18) (n = 3) (n = 3) (n = 3) (n = 3) (n = 6)
Blood urea nitrogen (mg/dL)
Baseline 12.04 ± 1.948 12.53 ± 3.459 12.17 ± 1.877 11.47 ± 0.907 10.80 ± 1.744 12.65 ± 1.854
 EOT/ET 13.13 ± 2.005 13.73 ± 1.415 12.07 ± 0.802 12.33 ± 0.987 13.17 ± 1.450 13.73 ± 3.108
Creatinine (mg/dL)
Baseline 0.78 ± 0.115 0.77 ± 0.115 0.77 ± 0.058 0.80 ± 0.000 0.67 ± 0.153 0.85 ± 0.122
 EOT/ET 0.79 ± 0.139 0.77 ± 0.115 0.73 ± 0.058 0.83 ± 0.058 0.70 ± 0.173 0.87 ± 0.175
Uric acid (mg/dL)
Baseline 5.38 ± 0.998 4.77 ± 1.079 6.23 ± 0.777 6.13 ± 1.021 4.80 ± 0.985 5.18 ± 0.788
 EOT/ET 5.34 ± 1.100 4.57 ± 1.242 6.17 ± 0.611 5.53 ± 0.379 5.00 ± 0.889 5.40 ± 1.453
Abbreviations: EOT = end of treatment; ET = early termination.
Data are presented as mean ± standard deviation.

Table 6. Specific Chemistry Profiles in Participants

All participants Dose level A Dose level B Dose level C Dose level D Dose level E
Variable (N = 18) (n = 3) (n = 3) (n = 3) (n = 3) (n = 6)
Total cholesterol (mg/dL)
Baseline 176.4 ± 29.07 192.0 ± 28.00 195.0 ± 36.10 188.3 ± 38.00 155.0 ± 27.87 164.0 ± 15.86
 EOT/ET 174.9 ± 33.94 197.7 ± 4.93 193.3 ± 46.26 176.7 ± 46.65 156.0 ± 33.51 163.0 ± 28.81
Triglyceride (mg/dL)
Baseline 75.4 ± 19.90 74.7 ± 6.66 69.7 ± 2.08 77.0 ± 17.06 60.3 ± 5.77 85.3 ± 30.35
 EOT/ET 83.0 ± 41.40 104.3 ± 47.25 64.3 ± 24.58 128.0 ± 60.26 47.3 ± 9.45 77.0 ± 26.50
C-reactive protein (CRP) (mg/dL)
Baseline 0.078 ± 0.0566 0.060 ± 0.0624 0.077 ± 0.0473 0.067 ± 0.0252 0.120 ± 0.0872 0.073 ± 0.0615
 EOT/ET 0.083 ± 0.0920 0.053 ± 0.0115 0.067 ± 0.0379 0.050 ± 0.0100 0.053 ± 0.0577 0.138 ± 0.1457
Glucose (fasting) (mg/dL)
Baseline 86.5 ± 5.27 91.0 ± 1.00 89.3 ± 1.15 82.7 ± 4.16 84.3 ± 6.51 85.8 ± 6.37
 EOT/ET 88.4 ± 5.32 88.7 ± 4.16 86.7 ± 5.51 89.3 ± 4.16 91.3 ± 9.29 87.2 ± 5.12
Amylase (U/L)
Baseline 52.3 ± 13.26 48.7 ± 15.57 56.3 ± 9.81 50.7 ± 19.66 54.3 ± 5.86 51.8 ± 16.50
 EOT/ET 52.8 ± 17.64 47.0 ± 12.77 50.0 ± 7.21 67.7 ± 38.66 51.0 ± 5.00 50.5 ± 14.10
Lipase (U/L)
Baseline 18.75 ± 12.495 27.33 ± 20.033 7.50 ± 8.322 18.33 ± 4.933 22.00 ± 18.248 18.67 ± 8.548
 EOT/ET 19.61 ± 11.073 24.00 ± 11.358 8.33 ± 4.041 24.67 ± 11.590 25.00 ± 16.523 17.83 ± 8.448
Abbreviations: EOT = end of treatment; ET = early termination.
Data are presented as mean ± standard deviation.

(Table 5), total cholesterol, triglycerides, C-reactive protein, basophils, which exhibited changes compared with the base-
fasting glucose, amylase, lipase (Table 6), and electrolyte line levels; however, these differences were not clinically
profiles (Table 7), were normal according to standard clinical significant. Of all AEs observed, 2 were mild and 2 were
safety references. Hematological profiles (Table 8) were moderate (data not shown) with headache and urticaria. No
within the normal range, except for eosinophils and serious AEs occurred. Moreover, the AE incidences at all
 Journal of the American College of Nutrition 279

Table 7. Electrolyte Profiles in Participants

All participants Dose level A Dose level B Dose level C Dose level D Dose level E
Variable (N = 18) (n = 3) (n = 3) (n = 3) (n = 3) (n = 6)
Phosphorus (mg/
dL)
Baseline 3.71 ± 0.295 3.60 ± 0.100 3.60 ± 0.458 3.80 ± 0.265 3.73 ± 0.252 3.77 ± 0.361
 EOT/ET 3.80 ± 0.314 3.87 ± 0.058 3.67 ± 0.473 3.83 ± 0.252 3.90 ± 0.265 3.77 ± 0.413
Potassium
(mmol/L)
Baseline 4.25 ± 0.359 4.37 ± 0.252 4.53 ± 0.577 4.40 ± 0.265 4.00 ± 0.173 4.10 ± 0.322
 EOT/ET 4.17 ± 0.216 4.17 ± 0.058 4.10 ± 0.300 4.17 ± 0.115 4.23 ± 0.351 4.18 ± 0.248
Calcium (mmol/L)
Baseline 2.38 ± 0.052 2.39 ± 0.050 2.39 ± 0.045 2.43 ± 0.015 2.34 ± 0.074 2.38 ± 0.050
 EOT/ET 2.37 ± 0.088 2.40 ± 0.074 2.38 ± 0.064 2.38 ± 0.087 2.31 ± 0.067 2.37 ± 0.121
Sodium (mmol/L)
Baseline 140.1 ± 1.43 139.3 ± 2.52 140.3 ± 0.58 140.0 ± 1.00 140.7 ± 0.58 140.0 ± 1.79
 EOT/ET 139.4 ± 2.28 139.7 ± 3.06 139.7 ± 2.08 137.7 ± 4.16 141.0 ± 1.00 139.2 ± 1.17
Magnesium
(mmol/L)
Baseline 0.89 ± 0.046 0.96 ± 0.030 0.86 ± 0.032 0.90 ± 0.021 0.89 ± 0.023 0.87 ± 0.044
 EOT/ET 0.89 ± 0.050 0.94 ± 0.040 0.88 ± 0.029 0.86 ± 0.064 0.93 ± 0.017 0.87 ± 0.049
Abbreviations: EOT = end of treatment; ET = early termination.
Data are presented as mean ± standard deviation.

Table 8. Hematology Profiles in Participants

All participants Dose level A Dose level B Dose level C Dose level D Dose level E
Variable (N = 18) (n = 3) (n = 3) (n = 3) (n = 3) (n = 6)
Hemoglobin (g/dL)
Baseline 14.07 ± 1.112 13.70 ± 1.311 14.33 ± 0.503 13.97 ± 0.896 13.50 ± 1.908 14.47 ± 1.061
 EOT/ET 14.17 ± 1.378 13.97 ± 1.976 14.40 ± 0.529 14.10 ± 0.781 13.33 ± 1.665 14.62 ± 1.646
Hematocrit (%)
Baseline 43.00 ± 3.228 41.93 ± 3.202 44.03 ± 2.686 42.87 ± 2.984 41.40 ± 5.533 43.88 ± 2.970
 EOT/ET 43.46 ± 4.151 43.43 ± 6.117 44.13 ± 3.126 42.93 ± 3.496 41.67 ± 5.793 44.30 ± 4.264
RBC (10 /µL)
6

Baseline 4.76 ± 0.407 4.63 ± 0.492 4.87 ± 0.619 4.71 ± 0.351 4.57 ± 0.529 4.90 ± 0.301
 EOT/ET 4.81 ± 0.484 4.75 ± 0.765 4.85 ± 0.630 4.74 ± 0.257 4.58 ± 0.565 4.97 ± 0.429
Platelet (103/µL)
Baseline 263.1 ± 41.01 274.0 ± 37.36 276.0 ± 56.93 261.3 ± 30.92 257.0 ± 51.68 255.2 ± 46.27
 EOT/ET 264.6 ± 45.07 248.3 ± 17.62 292.3 ± 32.88 247.0 ± 41.61 264.7 ± 72.86 267.7 ± 52.11
WBC (103/µL)
Baseline 5.97 ± 1.543 4.79 ± 1.177 6.49 ± 0.616 5.92 ± 2.942 5.54 ± 0.396 6.53 ± 1.540
 EOT/ET 6.05 ± 1.545 5.25 ± 1.380 6.60 ± 0.977 5.41 ± 0.981 5.35 ± 0.703 6.84 ± 2.130
Neutrophils (%)
Baseline 57.33 ± 7.189 49.53 ± 8.961 54.90 ± 1.253 62.87 ± 9.693 59.77 ± 6.354 58.45 ± 5.073
 EOT/ET 54.61 ± 7.416 53.80 ± 8.664 53.17 ± 2.540 56.23 ± 10.897 59.77 ± 5.835 52.35 ± 8.245
Lymphocytes (%)
Baseline 33.04 ± 6.085 39.97 ± 8.041 35.50 ± 1.652 27.10 ± 3.804 30.60 ± 6.089 32.55 ± 4.569
 EOT/ET 33.25 ± 6.796 36.10 ± 10.859 36.23 ± 2.854 31.07 ± 5.729 29.43 ± 6.529* 33.33 ± 7.389
Monocytes (%)
Baseline 5.84 ± 1.703 5.27 ± 0.643 5.67 ± 1.201 7.33 ± 3.721 5.43 ± 0.850 5.67 ± 1.266
 EOT/ET 5.56 ± 1.809 5.60 ± 2.022 5.37 ± 0.586 7.50 ± 3.274 5.50 ± 1.308 4.68 ± 1.082
Eosinophils (%)
Baseline 3.05 ± 2.396 4.27 ± 4.876 3.23 ± 1.332 2.20 ± 2.307 3.40 ± 2.685 2.60 ± 1.624
 EOT/ET 5.77 ± 6.932 3.80 ± 3.747 4.37 ± 1.185 4.60 ± 2.869* 3.97 ± 1.858 8.93 ± 11.587
Basophils (%)
Baseline 0.74 ± 0.387 0.97 ± 0.651 0.70 ± 0.361 0.50 ± 0.361 0.80 ± 0.173 0.73 ± 0.393
 EOT/ET 0.82 ± 0.429 0.70 ± 0.693 0.87 ± 0.351* 0.60 ± 0.346 1.33 ± 0.416 0.70 ± 0.228
Abbreviations: EOT = end of treatment; ET = early termination; RBC = red blood cells; WBC = white blood cells.
Data are presented as mean ± standard deviation.
*Dose level was significantly different with baseline, p < 0.05.

dose levels (A to E) were 0.0%, 33.3%, 33.3%, 0.0%, and Only cortisol at dose level E changed from baseline (10.78
33.3%, with no dose-dependent increase in incidence asso- vs 8.17 µg/dL); however, this change was not clinically sig-
ciated with LEAC-102 administration (Table 9). nificant (Table 10).
We focused on the possible immunomodulatory activities
of LEAC-102 by characterizing the immune profiles of partic-
Exploratory profiles
ipants in the indicated cohorts (C to E), including protective
The exploratory safety end points, including ACTH, pro- immune effector cells and suppressive regulatory cells, before
gesterone, testosterone, and E2 levels, were within the nor- treatment and 1 month after LEAC-102 administration. All
mal range according to standard clinical safety references. immune profiling analyses depicted the difference in each dose
280 Y.-T. LIAO ET AL.

Table 9. AEs in Participants Receiving the Dose of LEAC-102

All participants Dose level A Dose level B Dose level C Dose level D Dose level E
(N = 18) (n = 3) (n = 3) (n = 3) (n = 3) (n = 6)
Participants Participants Participants Participants Participants Participants
System organ class n % n % n % n % n % n %
Overall 4 22.2 0 0.0 1 33.3 1 33.3 0 0.0 2 33.3
Atrioventricular block, 1 5.6 0 0.0 0 0.0 1 33.3 0 0.0 0 0.0
first-degree
Blood bilirubin increased 1 5.6 0 0.0 1 33.3 0 0.0 0 0.0 0 0.0
Headache 1 5.6 0 0.0 0 0.0 0 0.0 0 0.0 1 16.7
Urticaria 1 5.6 0 0.0 0 0.0 0 0.0 0 0.0 1 16.7
The adverse event (AE) incidence rate is defined as 100%. n = The number of participants with an event. N = the number of participants in the dose level group.

Table 10. Specific Hormones in Participants

All participants Dose level A Dose level B Dose level C Dose level D Dose level E
Variable (N = 18) (n = 3) (n = 3) (n = 3) (n = 3) (n = 6)
Adrenocorticotropin (pg/mL)
Baseline 17.25 ± 5.883 21.53 ± 4.366 20.57 ± 7.177 13.38 ± 8.391 16.37 ± 3.485 15.82 ± 5.184
 EOT/ET 19.22 ± 10.446 26.78 ± 23.037 18.62 ± 10.434 16.83 ± 6.503 15.20 ± 7.021 18.93 ± 5.550
Cortisol (ug/dL)
Baseline 9.05 ± 2.425 8.77 ± 2.860 8.80 ± 1.868 9.10 ± 1.970 11.30 ± 3.464 8.17 ± 2.216
 EOT/ET 11.51 ± 5.284* 10.67 ± 5.040 7.47 ± 3.147 16.93 ± 10.289 12.40 ± 3.161 10.78 ± 2.340*
Progesterone (ng/mL)
Baseline 2.81 ± 4.598 3.82 ± 3.356 0.39 ± 0.039 0.21 ± 0.110 3.86 ± 6.011 4.28 ± 6.439
 EOT/ET 1.29 ± 2.613 0.31 ± 0.106 0.34 ± 0.083 3.82 ± 6.047 0.39 ± 0.095 1.434 ± 1.767
Testosterone (ng/mL)
Baseline 3.19 ± 2.940 1.20 ± 1.582 5.60 ± 1.149 2.01 ± 2.939 3.38 ± 4.895 3.47 ± 2.832
 EOT/ET 3.54 ± 3.254 1.94 ± 2.933 6.58 ± 1.518 2.23 ± 3.225 3.47 ± 5.391 3.50 ± 2.780
Estradiol (pg/mL)
Baseline 75.54 ± 80.035 56.67 ± 23.963 28.73 ± 6.030 101.60 ± 132.876 97.13 ± 114.211 84.55 ± 83.319
 EOT/ET 57.18 ± 52.701 51.77 ± 28.446 27.67 ± 4.252 90.47 ± 111.335 34.53 ± 7.401 69.33 ± 49.419
Abbreviations: EOT = end of treatment; ET = early termination.
Data are presented as mean ± standard deviation.
*Dose level was significantly different with baseline, p < 0.05.

group in terms of the percentage change between baseline and higher than at baseline, but it was within the clinical normal
EOT. The number of NK cells was significantly increased in range and was not dose-dependent. A pilot study also
a dose-dependent (level C to E) manner after LEAC-102 treat- revealed that AC significantly reduced systolic blood pres-
ment (−26.0%, −1.6%, and 12.1%, respectively [p = 0.04]) sure (from 144.86 to 133.10 mm Hg, p < 0.05) and diastolic
(Figure 1D). Cohorts D and E also demonstrated a trend of blood pressure (from 96.19 to 91.38 mm Hg, p < 0.05) in
monocyte (10.2%, 6.3%), natural killer T (NKT) cell (−2.8%, mildly hypertensive patients who were administered AC for
17.9%), and dendritic cell (DC) (−13.1%, −1.9%) induction 2 months with no abnormal laboratory findings (18).
compared to that of cohort C (Figure 2A–F). Furthermore, Furthermore, the changes in parameters, such as total bil-
increased levels of programmed cell death-1 (PD-1) expressed irubin (from 0.85 to 0.67 mg/dL) in liver function assess-
on naive CD4+ T cells (27.2%, 61.9%), naive CD8+ T cells ments and lymphocytes (from 30.60% to 29.43%), eosinophils
(56.2%, 67.0%), and activated CD4+ T cells (103.1%, 235.6%) (from 2.20% to 4.60%), and basophils (from 0.70% to 0.87%)
were noted upon administration of doses D and E of LEAC-102 in hematological assessments, were also not clinically sig-
(Figure 3A–D). nificant. This finding is consistent with the toxicological
research results of AC administration to date, and even
when used as a health food, AC can protect the liver and
enhance immunity (15, 19–21).
Discussion
Although AC is regarded as a Chinese herbal medicine
This was a first-in-human study of LEAC-102, an emerging with biological effects, its clinical safety is still unclear.
botanical drug extracted from the fruiting bodies and Thus, the therapeutic application of AC needs to be eval-
solid-state cultivated mycelia of AC. The results demon- uated in formal and government-approved human clinical
strated that oral administration of LEAC-102 at dosages up trials to determine its safety and tolerability. Several tox-
to 2988 mg/day was well tolerated by healthy adults. A sim- icological tests indicated that AC doses up to 4000 mg/kg
ilar observation was made in a preliminary study, in which body weight/day in rats (22, 23) and 2500 mg/kg body
healthy adults ingested AC products at a dosage of 1440 mg weight/day in mice were safe and tolerable as no significant
daily for 3 months with normal clinical biochemistry profiles abnormalities were observed in body weight, organ weight
and no AEs (5). A few changes were noted overall during gain, hematological parameters, and liver and renal func-
our trial. The systolic blood pressure in dose groups A and tion (23, 24). In our study, we strictly monitored the effect
C (equivalent to 597.6 and 1792.8 mg/day) was significantly of all LEAC-102 doses on renal function. Only in terms
 Journal of the American College of Nutrition 281

Figure 2. Distribution of immune cells during LEAC-102 treatment in participants at doses C to E. (A) B cells, (B) monocytes, (C) dendritic cells, (D) natural
killer (NK) cells, (E) NKT cells, and (F) T cells in peripheral blood mononuclear cells (PBMCs) were quantified by flow cytometry using antibodies against specific
epitopes. The percentages of the indicated cell subsets and statistical significance between groups were analyzed and calculated using Kazula and Prism
(*p < 0.05, **p < 0.01, ***p < 0.001).

Figure 3. LEAC-102 upregulates programmed cell death-1 (PD-1) expression on CD4+ and CD8+ T cells in the peripheral blood. Participants were administered
LEAC-102 at doses of C, D, or E (1792.8, 2390.4, or 2988 mg/day) for 1 month. (A) Naive PD-1+ CD4+ T cells, (B) activated PD-1+ CD4+ T cells, (C) naive PD-1+
CD8+ T cells, and (D) activated PD-1+ CD8+ T cells were quantified by flow cytometry using antibodies against specific epitopes. The percent changes in the
indicated cell subsets and statistical significance between groups were analyzed and calculated by Kazula and Prism (*p < 0.05, **p < 0.01, ***p < 0.001).

of adrenal function did the cortisol level at dose E increase including ultrasound of the adrenal gland (data not shown)
to 10.78 µg/dL at the end point; however, this was not a and serum hormone and electrolyte profiling, all confirmed
clinically significant finding. The remaining parameters, the safety of LEAC-102.
282 Y.-T. LIAO ET AL.

increases splenic lymphocyte proliferation by activating

the c-JUN N-terminal kinase, p38, and extracellular
signal-regulated kinase signaling pathways (25–27).
Another study revealed that polysaccharides extracted
from AC play a crucial role in the activation of DCs,
critical leukocytes for initiating immune responses, in
mice (28). AC treatment also increased the capacity of
activated DCs to suppress allergen-specific type 2 T
helper cell polarization in an allogeneic mixed lympho-
cyte reaction (29). Moreover, our study shows for the
first time that LEAC-102 promotes CD4 + T and CD8 + T
cell activation accompanied by the upregulation of PD-1
expression by CD4 + and +CD8 + T cells. Immune check-
point inhibitors targeting PD-1 have been widely inves-
tigated, and PD-1 +CD4 + and PD-1 +CD8 + effector cells
Figure 4. A potential effect on immune regulation during LEAC-102 treatment play a crucial role in advanced cancer therapy (30, 31).
in healthy participants. LEAC-102 increases naive CD4+ T cells, effector CD4+ T Thus, taking LEAC-102 increases naive CD4+ T cells and
cells, and naive CD8+ T cells, then effector CD4+ T cells also stimulate naive activates effector CD4 + T cells, then stimulates naive
CD8+ T cells. Moreover, CD4+ and CD8+ T cell activation is accompanied by CD8 + T cells, meaning that LEAC-102 may have an edu-
the upregulation of programmed cell death-1 (PD-1) expression by CD4+ and
cation effect on immune system (Figure 4) and exhibits
CD8+ T cells, both indicating that taking LEAC-102 may have an education
effect on the immune system in healthy participants. multiple effects important for adjuvant cancer treatment.
Although this study provides important data on the clin-
ical safety and potential immune efficacy profile of
Single dosing with LEAC-102 up to 2988 mg/day has no LEAC-102, there are still some limitations. All data were
serious adverse effects on healthy adults; however, one of obtained from healthy participants who only received an
the participants experienced urticaria and DLT. This par- oral dose of up to 2988 mg/day, which limits the general-
ticipant was a 32-year-old man and was enrolled on izability of findings. Moreover, the small sample size with
September 4, 2019; no medical history was noted for this the 3 + 3 dose-escalated design may limit the evaluation of
person at the screening. Then, the participant was assigned immunomodulatory potential.
to cohort E from September 17 to 26, 2019. The participant The purpose of this study was to evaluate the tolerability
experienced moderate urticaria on September 25, 2019, and of LEAC-102 in healthy participants and observe DLT. If
the dosing of LEAC-102 was held from the evening on LEAC-102 is to be used in cancer adjuvant applications,
September 26, 2019. Without additional medication given further research is needed on the safety, tolerability, phar-
to treat this event, this event was recovered on September macokinetics, pharmacodynamics, and efficacy of LEAC-102
30, 2019, after stopping the dosing of LEAC-102. This par- in patients with cancer.
ticipant was then withdrawn from the study on October 1,
2019, by the investigator. The dosing of LEAC-102 was
interrupted and then withdrawn in this participant due to Conclusions
this event; this event was possibly related to LEAC-102 as
judged by the investigator and was considered a DLT. This first-in-human phase I study of LEAC-102 demon-
Therefore, the MTD in this study was determined to be strated an acceptable safety and tolerability profile at doses
dose level E, in which participants were administered up to 2988 mg/day with no serious adverse effects in healthy
2988 mg/day of LEAC-102 for 28 consecutive days. A total adults. Our results suggested that LEAC-102 may exhibit
of 4 AEs were observed in 4 participants in this study, novel immunomodulatory activities by promoting adaptive
including increased blood bilirubin, first-degree atrioven- T-cell activation and simultaneously upregulating PD-1
tricular block, urticaria, and headache. All AEs were expression in a dose-dependent manner. Based on these
resolved, except for one in a participant who had a high findings, LEAC-102 is expected to be applicable for cancer
bilirubin level at enrollment that appeared to decrease at treatment and has the potential to shed light on mechanisms
the end of the study. However, the cause of preexisting high targetable by future immunotherapies.
bilirubin in this participant was not clear.
To investigate the potential immunomodulatory effects
of LEAC-102, we used epitope-specific antibodies and Acknowledgements
flow cytometric analysis to identify immune cell subsets
The authors would like to thank the participating volunteers and their
in the peripheral blood. Immune analysis revealed that
families for taking part in the study, all coinvestigators, and the
LEAC-102 dramatically promoted the induction of NK clinical and nursing staff for conducting the study. None of the authors
cells, NKT cells, and DCs in a dose-dependent manner. of this paper has a financial or personal relationship with other
Previous studies have shown that AC enhances NK cell individuals or organizations that could inappropriately influence or
cytolytic activity and macrophage phagocytic activity and bias the content of this paper.
 Journal of the American College of Nutrition 283

Disclosure statement 8. Huang C-H, Chang Y-Y, Liu C-W, Kang W-Y, Lin Y-L, Chang
H-C, Chen Y-C. Fruiting body of Niuchangchih (Antrodia cam-
We confirm that there are no known conflicts of interest associated phorata) protects livers against chronic alcohol consumption
with this publication and there has been no significant financial support damage. J Agric Food Chem. 2010;58(6):3859–66. doi:10.1021/
for this work that could have influenced its outcome. jf100530c.
9. Liu YW, Lu KH, Ho CT, Sheen LY. Protective effects of Antrodia
cinnamomea against liver injury. J Tradit Complement Med.
2012;2(4):284–94.
Funding 10. Shih YL, Wu MF, Lee CH, et al. Antrodia Cinnamomea reduces
carbon tetrachloride-induced hepatotoxicity in male wister rats.
The study was supported by Taiwan Leader Biotech Corp. Ltd. In Vivo (Athens, Greece). 2017;31:877–84.
11. Hsu YL, Kuo YC, Kuo PL, Ng LT, Kuo YH, Lin CC. Apoptotic
effects of extract from Antrodia camphorata fruiting bodies in
human hepatocellular carcinoma cell lines. Cancer Lett.
Role of the funding source 2005;221(1):77–89. doi:10.1016/j.canlet.2004.08.012.
12. Huang Y-J, Yadav VK, Srivastava P, Wu AT, Huynh T-T, Wei
The funding source had no involvement in the study design; data P-L, Huang C-YF, Huang T-H. Antrodia cinnamomea enhances
collection, analysis, or interpretation; writing of the report; or the chemo-sensitivity of 5-FU and suppresses colon tumorigenesis and
decision to submit the article for publication. The role of the funding cancer stemness via up-regulation of tumor suppressor miR-142-
source is the provision of test reagents and funds for the clinical trial. 3p. Biomolecules. 2019;9(8):306. doi:10.3390/biom9080306.
13. Su Y-K, Shih P-H, Lee W-H, Bamodu OA, Wu ATH, Huang
C-C, Tzeng Y-M, Hsiao M, Yeh C-T, Lin C-M, et al. Antrodia
Authors’ contributions cinnamomea sensitizes radio-/chemo-therapy of cancer stem-like
cells by modulating microRNA expression. J Ethnopharmacol.
Conception and design: Kai-Wen Huang. 2017;207:47–56. doi:10.1016/j.jep.2017.06.004.
Development of methodology: Tzung-Hsien Lai. 14. Liu J-J, Huang T-S, Hsu M-L, Chen C-C, Lin W-S, Lu F-J, Chang
Acquisition of data (acquired and managed patients, provided facilities, W-H. Antitumor effects of the partially purified polysaccharides
etc.): Yu-Tso Liao. from Antrodia camphorata and the mechanism of its action. Toxicol
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, Appl Pharmacol. 2004;201(2):186–93. doi:10.1016/j.taap.2004.05.016.
computational analysis): Tzung-Hsien Lai, Wan-Jing Chen. 15. Li TY, Chiang BH. 4-Acetylantroquinonol B from Antrodia cin-
namomea enhances immune function of dendritic cells against
Writing, review, and/or revision of the manuscript: Wan-Jing Chen,
liver cancer stem cells. Biomed Pharmacother. 2019;109:2262–9.
Yu-Tso Liao, Kai-Wen Huang.
16. Long H, Hu CT, Weng CF. Antrodia Cinnamomea prolongs sur-
Administrative, technical, or material support (i.e., reporting or orga-
vival in a patient with small cell lung cancer. Medicina (Kaunas,
nizing data, constructing databases): Yu-Tso Liao. Lithuania. 2019;55(10):640. doi:10.3390/medicina55100640.
Study supervision: Kai-Wen Huang. 17. Lin J-Y, Chen M-C, Chiu E. Genotoxicity and subchronic tox-
icity studies of Taiwanofungus camphoratus extract. Fundam
Toxicol Sci. 2019;6(3):81–106. doi:10.2131/fts.6.81.
ORCID 18. Chen CC, Li IC, Lin TW, Chang HL, Lin WH, Shen YC. Efficacy
and safety of oral Antrodia cinnamomea mycelium in mildly
Wan-Jing Chen http://orcid.org/0000-0003-0086-4231 hypertensive adults: a randomized controlled pilot clinical study.
Eur J Integr Med. 2016;8(5):654–60. doi:10.1016/j.eu-
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