Download Honokiol IN THE Integrative TREATMENT OF CANCER

HONOKIOL IN THE
INTEGRATIVE
TREATMENT OF
CANCER
INTRODUCTION:
HISTORY OF HONOKIOL
Magnolia Bark Extract

Extracts from the tree bark of the genus Magnolia have
been used for over 2,000 years in traditional Chinese (as
Hou Po) and Japanese medicines (as Saiboku-to) to treat
a variety of gastrointestinal disorders, neurological
diseases, including anxiety, depression, and seizures
TCM properties: Bitter, acrid, warm, aromatic
 Channels: Large intestine, lung, spleen, stomach


The active ingredients in the extracts have been
identified as the bi-phenolic isomers magnolol and
honokiol
Magnolol and Honokiol Isomers

As honokiol exists naturally with its structural isomer
magnolol, which differs from honokiol only by the position of
one hydroxyl group, purification has often been limited

Methods developed since 2006, are now able to simply purify
the honokiol active ingredient away from the more
predominate less active magnolol
MAGNOLIA OFFICINALIS EXTRACT: 98%
PURIFIED HONOKIOL
Botanical Compound
Honokiol in the
Treatment of Cancer
Honokiol Properties
Properties
 Anti-inflammatory
 Antioxidant
 Selective Pro-oxidant
 Anti-Microbial
 Anti-Tumor (Induces Apoptosis &
Cell Cycle Arrest)
 Anti-Angiogenic
 Anti-Anxiety/Insomnia
 Neuroprotective
 Synergistic Anticancer Effect w/ Multiple Chemotherapy Drugs
 Crosses the Blood–Brain Barrier, Candidate for the Treatment of
Central Nervous System Primary Tumors and Metastases
 No Appreciable Toxicity
THE MECHANISMS OF
ACTION
Honokiol – Main Mechanisms of Action

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Blocks signaling in tumors with defective p53
function and activated Ras by blocking activation
of phospholipase D
Induces cyclophilin D, potentiating mitochondrial
permeability transition pore and causing death in
cancer cells with wild-type p53
Blocks NF-kB activation
Inhibits mTORcomplex1
Inhibits ROS production
Modulates GABA receptors
IN VIVO AND IN VITRO
ANTITUMOR ACTIVITY OF
HONOKIOL
Extensive Preclinical Oncology
Research has Shown that Honokiol:



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

Inhibits nitric oxide synthesis and tumor necrosis
factor (TNF) expression
Inhibits invasive behavior
Down-regulates antiapoptotic protein Bcl-xL
Inhibits angiogenesis and tumor growth in vivo
Induces caspase dependent apoptosis through
down-regulation of the antiapoptotic protein Mcl-1
Overcomes drug resistance in multiple myeloma
Extensive Preclinical Oncology Research
has Shown that Honokiol (Continued):



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Potentiates the apoptotic effects of TNF and
chemotherapeutic drugs
Suppresses induced osteoclastogenesis
Suppresses TNF-induced tumor cell invasion
activity
Blocks NF-kB activation induced by various agents
Suppresses NF-kB activation in a dose-and timedependent manner
Inhibits constitutive NF-kB activation
Honokiol Anti-Tumor Gene & Protein
Expression Modulation

Up regulated
 p21 & p27
 Tyrosine Phosphatase
SHP-1
 Cytosolic Cytochrome C
 Greater Caspase Activity
 Bax (pro-apoptotic
protein)
 Bak (pro-apoptotic
protein)
 Glucose-Regulated
Protein 78 (GRP78)
 Calpain
 Caspase-3, 8, 9
 Poly (ADP-ribose)
Polymerase (PARP)
 p53 Activation (tumor
suppressor gene)
Honokiol Anti-Tumor Gene & Protein
Expression Modulation

Down regulated or inhibited
 Cyclin D1, D2, E, A1
 Cyclin-Dependent Kinases
2, 4, 6
 Kinases C-Src
 Janus-Activated Kinase 1, 2
 Nuclear Factor-κB (NF-κB)
and Inducible Nitric Oxide
Synthases (iNOS)
 HIF-1α
 Cyclooxygenase-2 (COX-2)
Prostaglandin (PG) E2
Peroxisome ProliferatorActivated Receptors –
Gamma (PPAR-Gamma)
 Mammalian Target of
Rapamycin Complex 1
(mTORC1)
 Bcl-xL
 EGFR Signaling
 Mitogen-Activated Protein
Kinase
 Akt
 Mcl-1

H
H
Huanli X, et al. Drug Discoveries
& Therapeutics. 2011; 5(5):202210
The extrinsic apoptosis pathway
involves ligation of death
receptors with their ligands,
resulting in a sequential
activation of caspase-8 and -3
Intrinsic death stimuli indirectly
activates the mitochondrial
pathway by inducing release of
cytochrome c and formation of
the apoptosome, which
consists of Apaf-1 and caspase9. Caspase-9 is activated at the
apoptosome and in turn
activates procaspase-3
Effects of honokiol (H) on extrinsic (receptor-mediated) & intrinsic
(mitochondria-mediated) apoptosis pathways in cancer
Nature Reviews Cancer 11, 85-95, 2011
Regulation of Cancer Cell Metabolism
mTOR Signaling
Selected Honokiol Cancer Research

Honokiol traverses the blood-brain barrier and induces
apoptosis of neuroblastoma cells via an intrinsic baxmitochondrion-cytochrome c-caspase protease pathway. Lin
JW, et al. Neuro Oncol. 2012 Jan 18

Anti-metastatic activity of honokiol in osteosarcoma.
Steinmann P, et al. Cancer. 2011 Sep 20. doi:
10.1002/cncr.26434

Honokiol arrests cell cycle, induces apoptosis, and
potentiates the cytotoxic effect of gemcitabine in human
pancreatic cancer cells. Arora S, et al. PLoS One.
2011;6(6):e21573
Selected Honokiol Cancer Research

Honokiol synergizes chemotherapy drugs in multidrug
resistant breast cancer cells via enhanced apoptosis and
additional programmed necrotic death. Tian W, et al. Int J
Oncol. 2012 Dec 14. doi:10.3892/ijo.2012.1739

Honokiol produces anti-neoplastic effects on melanoma cells
in vitro. Mannal PW, et al. J Surg Oncol. 2011 Sep
1;104(3):260-4

Honokiol radiosensitizes colorectal cancer cells: enhanced
activity in cells with mismatch repair defects. He Z, et al. Am
J Physiol Gastrointest Liver Physiol. 2011 Nov;301(5):G929-37
Selected Honokiol Cancer Research

Apoptosis induced by Magnolia grandiflora extract in
chlorambucil-resistant B-chronic lymphocytic leukemia
cells. Marin GH, Mansilla E. J Cancer Res Ther. 2010 OctDec;6(4):463-5

Modulation of multidrug resistance p-glycoprotein activity
by flavonoids and honokiol in human doxorubicin-resistant
sarcoma cells (MES-SA/DX-5): implications for natural
sedatives as chemosensitizing agents in cancer therapy.
Angelini A, et al. J Biol Regul Homeost Agents. 2010 AprJun;24(2):197-205

Honokiol induces paraptosis and apoptosis and exhibits
schedule-dependent synergy in combination with imatinib
in human leukemia cells. Wang Y, Yang Z, Zhao X. Toxicol
Mech Methods. 2010 Jun;20(5):234-41
Effect of Honokiol on Growth of PC3
Cells (Pre-Published Data)
Honokiol Reviews

Honokiol, a multifunctional tumor cell death inducer. Tian
W, et al. Pharmazie. 2012 Oct;67(10):811-6

Honokiol, a multifunctional antiangiogenic and antitumor
agent. Fried LE, Arbiser JL. Antioxid Redox Signal. 2009
May;11(5):1139-48
Effect of Honokiol on the Growth of
MDA-MB-231 Cells (Pre-Published Data)
Synergistic Effect of Modified Citrus Pectin (MCP) & 98%
Honokiol on PC3 Cell line Migration (Pre-Published Data)
%Migration of PC3 Cells
100
90
80
70
60
50
40
30
20
10
0
Control
MCP 1 mg/ml MCP 2 mg/ml
MCP 4
mg/ml
%98 Honokiol MCP 1 mg/ml
20um
+ %98
Honokiol
20um
Effect of Honokiol on the Growth of 786-0 and A-498 Human
Renal Cell Carcinoma 786-0Cells (Pre-Published Data)
120
100
80
% Proliferation 60
40
20
0
24 hrs
48 hours
72 hours
EFFECT OF HONOKIOL ON
REACTIVE OXYGEN SPECIES
The Inhibition by Honokiol of
Reactive Oxygen Driven Tumors

Due to its involvement with the NADPH oxidase
(NOX) pathway.
 This
inhibition was first demonstrated
 in
neutrophils
 in hepatocytes
 Human Umbilical Vein Endothelial Cells (HUVECs)

NF-kB regulates the signaling pathway of NOXmediated oxidative stress
Honokiol Improves the Functions of
Normal Human Cells
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Results of oxygen consumption and malondialdehyde
(MDA) production showed that the honokiol inhibition
was 1,000 times that of α-tocopherol (vitamin E)
As honokiol is better than α-tocopherol at inhibiting
lipid peroxidation, it was used to protect the
myocardium against ischemic injury by suppressing
ventricular arrhythmia during ischemia and
reperfusion
Studies have shown the protective effect of honokiol
on hepatocytes from peroxidative injury, oxygen
consumption, and malondialdehyde formation
Honokiol has Both Pro- and
Antioxidant Activities

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Honokiol has antioxidant activities because the allyl
groups on honokiol can react with reactive oxygen
species
Also the anti-mitochondrial effects of honokiol
generates reactive oxygen by activating the
mitochondrial permeability transition pore. The
ability of honokiol to activate the mitochondrial pore
may be dependent on the p53 status, with tumors
with wild-type p53 having greater susceptibility to
pore formation
IMMUNE & ANTIINFLAMMATORY EFFECTS
OF HONOKIOL
Targeting the Intrinsic Inflammatory Pathway: Honokiol Exerts
Proapoptotic Effects Through STAT3 Inhibition in Transformed
Barrett's Cells

Yu C, et al. Am J Physiol Gastrointest Liver Physiol. 2012
Sep 1;303(5):G561-9
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Signal transducer and activator of transcription 3 (STAT3)
contributes to the intrinsic inflammatory pathway in Barrett's
esophagus.
In human tumors, honokiol has growth-inhibitory and
proapoptotic effects associated with suppressed activation of
STAT3
Honokiol causes necrosis and apoptosis in transformed
Barrett's and esophageal adenocarcinoma cells, but not in
nontransformed Barrett's cells, and the proapoptotic effects
of honokiol are mediated by its inhibition of STAT3 signaling.
Honokiol, a Natural Plant Product, Inhibits Inflammatory
Signals & Alleviates Inflammatory Arthritis

Munroe ME, et al. J Immunol 179: 753–763, 2007
 Treatment
with honokiol significantly decreased the
clinical scores of collagen-induced arthritis in both
normal and transgenic mice
 Antibody production, most notably IgG3, was
diminished, as were IL-12, IL-6, interferon gamma, and
notably IL-17
 These findings indicate that honokiol may have benefit
against IL-17–mediated inflammatory disorders,
including rheumatoid arthritis, psoriasis, and
inflammatory bowel disease
NEUROLOGIC EFFECTS OF
HONOKIOL
GABA (γ-Aminobutyric acid)
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The major inhibitory neurotransmitter in the central
nervous system
GABA acts at inhibitory synapses in the brain by
binding to specific transmembrane receptors in the
plasma membrane of neuronal processes
It is synthesized in the brain from glutamate using the
enzyme L-glutamic acid decarboxylase and pyridoxal
phosphate (active form of vitamin B6) as a cofactor via
a metabolic pathway called the GABA shunt.
Increase in the available amount of GABA typically
have relaxing, anti-anxiety, and anti-convulsive effects
GABA is synthesized from glutamate in a reaction
catalyzed by glutamic acid decarboxylase (GAD)
"GABA Shunt"
GABA Production Enhancers
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Taurine helps breakdown glutamate to GABA
Lysine enhances GABA action
Manganese is essential for glutamine synthesis
Pyridoxine (Vitamin B6) is an essential cofactor for
the GABA producing enzyme L-glutamic acid
decarboxylase (GAD)
Honokiol, a Putative Anxiolytic Agent Extracted from
Magnolia Bark, has No Diazepam-Like Side-Effects in Mice

Kuribara H, et al. J Pharm Pharmacol. 1999
Jan;51(1):97-103
 Results
suggest that honokiol is less likely than
diazepam to induce physical dependence, central
depression and amnesia at doses eliciting the
anxiolytic effect. It is also considered that honokiol
might have no therapeutic effect in the treatment of
convulsion
Effect of Honokiol on Activity of GAD(65) and
GAD(67) in the Cortex and Hippocampus of Mice

Ku TH, et al. Phytomedicine. 2011 Oct 15;18(13):1126-9

Mice treated with daily injection for 7 days of honokiol caused
anxiolytic action which was similar to that was induced by 7
daily injection of diazepam in a elevated plus-maze test. In
addition, the activity of hippocampal glutamic acid
decarboxylase GAD(65) of honokiol treated mice was
significantly increased than that of the vehicle or diazepam
treated groups. These data suggest that honokiol causes
diazepam-like anxiolytic action, which may be mediated by
altering the synthesis of GABA in the brain of mice
HONOKIOL
ANTIMICROBIAL ACTIVITY
Antimicrobial Activity of Magnolol and Honokiol
against Periodontopathic Microorganisms

Chang B, et al. Planta Med. 1998 May;64(4):367-9
 Honokiol
has been used to treat such
periodontopathic microorganisms as
 Porphyromonas gingivalis
 Prevotella gingivalis
 Actinobacillus actinomycetemcomitans
 Capnocytophaga gingivalis
 Veillonella disper
 No
cytotoxicity against human gingival fibroblasts and
epithelial cells; along with other gram-positive bacteria and
fungi
Antimicrobial and Cytotoxic Activities of
Neolignans from Magnolia officinalis

Syu WJ, et al. Chem Biodivers 1: 530–537, 2004
 Honokiol
has been used to inhibit the growth of
vancomycin-resistant enterococci (VRE) and
methicillin-resistant Staphylococcus aureus (MRSA), in
a dose-and time-dependent manner
HOW DO I USE
HONOKIOL?
Honokiol in Cancer Treatment

Anti-Cancer Effects

Enhancement

Protectant
Combination and Synergy

Chemotherapy
 Cisplatin,
Doxorubicin, Imatinib, Chlorambucil,
Gemcitabine, Adriamycin

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Heat Therapy
Radiation Therapy (Honokiol enhances the sensitivity
of cancer stem cells to ionizing radiation)
 Honokiol
in combination with radiation targets notch
signaling to inhibit colon cancer stem cells. Ponnurangam
S, et al. Mol Cancer Ther. 2012 Apr;11(4):963-72

Metabolism
Honokiol Dosages
Active Cancer: Build up to 1 g X 3/day starting with 250 mg x 3
times a day
Prevention and Post Therapy: 1 g/day
Anti-inflammatory and Circulation Support: 250 mg x 2/day to
500 mg x 2/day
Periodontal disease: 500 mg x 2/day until
condition improves, then 250 mg x 2/day
Antioxidant: 250 mg x 2/day
Anxiety: 250 mg x 2/day
Sleep: 250 mg before bed
Side Effects & Tolerance
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No appreciable side effects
Usually well tolerated
Side effect (dose dependent)
 Diarrhea
 Possible

stomach discomfort
Reversed with warming herbs
 ginger,
cardamom, etc.
Summary
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Honokiol has broad antitumor activity
Exhibits a desirable spectrum of bioavailability
Crosses the blood–brain barrier
Found also to have antioxidant, immune, antiinflammatory, neuroprotective, anxiolytic, and
antimicrobial action
Honokiol is an anti-stress agent and a potent
suppressor of oxidative damage and cancer
No appreciable toxicity
Now available as a purified 98% honokiol extract